Tricyclic amine derivatives

ABSTRACT

The present invention relates to a compound having a tricyclic amine substituent which may have various substituents, the compound being represented by formula (I), a salt or hydrate thereof, and a hydrate of the salt and a drug containing them as an active ingredient. They exhibit excellent antimicrobial activity against Gram negative bacteria and Gram positive bacteria with a satisfactory fate and safety and are useful in the treatment of infectious diseases.                    
     wherein Q preferably represents the following partial structure which may have various substituents:

INDUSTRIAL FIELD

This invention relates to an antimicrobial compound useful as a drug forhumans, animals or fishes or an antimicrobial preservative and anantimicrobial agent or preparation containing the same.

BACKGROUND ART

Since the discovery of Norfloxacin, synthetic quinolone antimicrobialagents have been improved in antimicrobial activity andpharmacokinetics, and many compounds have been launched for clinical useas a chemotherapeutic agent effective on all most all systemicinfectious diseases.

However, bacteria having low sensitivity to the synthetic quinoloneantimicrobial agents have recently been increasing in the clinicalfield. For example, bacteria which have not only resistance to drugsother than synthetic quinolone antimicrobial agents but low sensitivityto synthetic quinolone antimicrobial agents, as exemplified byStaphylococcus aureaus insensitive to β-lactam antibiotics (MRSA), havebeen increasing. Therefore, more effective drugs have been keenlydemanded in the field of clinics.

Further, it has been revealed that synthetic quinolone antimicrobialagents tend to induce convulsion in a combined use with a non-steroidantiinflammatory agent or involve side effects such as phototoxicity.Therefore, development of safer synthetic quinolone antimicrobial agentshas been sought.

DISCLOSURE OF THE INVENTION

In the light of these circumstances, the inventors have conductedextensive investigation for the purpose of providing excellent compoundsfulfilling the above demands. As a result, they have found thattricyclic amine derivatives represented by formula (I) shown below andtheir salts and hydrates thereof have high antimicrobial activitybroadly on Gram positive bacteria and Gram negative bacteria, exhibitingpotent antimicrobial activity particularly on quinolone-resistantbacteria including MRSA, and also show satisfactory pharmacokinetics andsafety.

The present invention relates to a compound represented by formula (I)shown below and its salt and their hydrates

wherein R¹ and R² each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms which may be substituted with oneor more substituents selected from the group consisting of a hydroxylgroup, a halogen atom, an alkylthio group having 1 to 6 carbon atoms,and an alkoxyl group having 1 to 6 carbon atoms;

R³ represents a hydrogen atom, a hydroxyl group, a halogen atom, acarbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxylgroup having 1 to 6 carbon atoms or an alkylthio group having 1 to 6carbon atoms, in which the alkyl group may be substituted with one ormore substituents selected from the group consisting of a hydroxylgroup, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;

R⁴ and R⁵ each independently represents a hydrogen atom, a halogen atom,an alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1to 6 carbon atoms, in which the alkyl group may be substituted with oneor more substituents selected from the group consisting of a hydroxylgroup, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;

R⁶ and R⁷ each independently represents a hydrogen atom or an alkylgroup having 1 to 6 carbon atoms;

X¹ represents an oxygen atom, a sulfur atom, a partial structure:

 (wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or2)

 or a partial structure:

 (wherein R¹⁰ represents a hydrogen atom, a formyl group, an acyl grouphaving 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbonatoms);

n represents an integer 1 or 2; and

Q represents a partial structure represented by formula:

 (wherein R¹¹ represents an alkyl group having 1 to 6 carbon atoms, analkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1to 6 carbon atoms, a substituted or unsubstituted cycloalkyl grouphaving 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, an alkoxyl group having 1to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms;

R¹² represents a hydrogen atom or an alkylthio group having 1 to 6carbon atoms;

R¹¹ and R¹² may be taken together with part of the mother skeleton towhich they are bonded to form a cyclic structure that may have a sulfuratom as a ring-constituting atom and an alkyl group having 1 to 6 carbonatoms as a substituent;

R¹³ represents a hydrogen atom, an amino group, a hydroxyl group, athiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbonatoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl grouphaving 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbonatoms, in which the amino group may have one or two substituentsselected from the group consisting of a formyl group, an alkyl grouphaving 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbonatoms;

X² represents a halogen atom or a hydrogen atom;

A¹ represents a nitrogen atom or a partial structure represented byformula (II):

 wherein X³ represents a hydrogen atom, an amino group, a halogen atom,a cyano group, a halogenomethyl group, a halogenomethoxyl group, analkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxylgroup having 1 to 6 carbon atoms, in which the amino group may have oneor two substituents selected from the group consisting of a formylgroup, an alkyl group having 1 to 6 carbon atoms and an acyl grouphaving 2 to 5 carbon atoms; and X³ and R¹¹ may be taken together withpart of the mother skeleton to which they are bonded to form a cyclicstructure that may contain an oxygen atom, a nitrogen atom or a sulfuratom as a ring-constituting atom and an alkyl group having 1 to 6 carbonatoms as a substituent;

A² and A³ each represents a nitrogen atom or a carbon atoms providedthat A², A³, and the carbon atom to which they are bonded form a partialstructure:

>C═C(A¹═)—N(R¹¹)—

 or a partial structure:

>N—C(A¹═)═C(R¹¹)—

wherein > indicates the carbon atom or the nitrogen atom has two bonds(hereinafter the same); and

Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, apivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, adimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group,an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having2 to 7 carbon atoms, or a phenylalkyl group composed of an alkylenegroup having 1 to 6 carbon atoms and a phenyl group).

The present invention also relates to:

(1) the compound of formula (I), wherein Q is a structure represented byformula:

 or a structure represented by formula:

 a salt or hydrate thereof, and a hydrate of the salt;

(2) the compound of formula (I), wherein Q is a structure represented byformula:

 a salt or hydrate thereof, and a hydrate of the salt;

(3) the compound of formula (I), wherein Q is a9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-6-carboxylicacid-10-yl group of formula:

 a salt or hydrate thereof, and a hydrate of the salt;

(4) the compound of formula (I), wherein Q is a6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinolin-3-carboxylicacid-7-yl group of formula:

 a salt or hydrate thereof, and a hydrate of the salt;

(5) the compound of formula (I), wherein Q is a6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinolin-3-carboxylicacid-7-yl group of formula:

 a salt or hydrate thereof, and a hydrate of the salt;

(6) the compound of formula (I), wherein Q is a5-amino-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinolin-3-carboxylicacid-7-yl group of formula:

 a salt or hydrate thereof, and a hydrate of the salt;

(7) the compound of formula (I), wherein X¹ is a partial structurerepresented by formula:

 wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or2,

 a salt or a hydrate thereof, and a hydrate of the salt;

(8) the compound of formula (I), wherein R⁸ and R⁹ are each a hydrogenatom, and m is 1, a salt or hydrate thereof, and a hydrate of the salt;

(9) the compound of formula (I), wherein n is 1, a salt or hydratethereof, and a hydrate of the salt;

(10) the compound of formula (I), wherein n is 1, and X¹ is a partialstructure represented by formula:

 wherein

R⁸ and R⁹ each independently represents a hydrogen atom or an alkylgroup having 1 to 6 carbon atoms, and m represents an integer 1 or 2,

 a salt or hydrate thereof, and a hydrate of the salt;

(11) the above compound in which R⁸ and R⁹ are each a hydrogen atom, asalt or hydrate thereof, and a hydrate of the salt;

(12) the above compound in which m is 1, a salt or hydrate thereof, anda hydrate of the salt;

(13) the above compound in which R⁸ and R⁹ are each a hydrogen atom, andm is 1, a salt and hydrate thereof, and a hydrate of the salt;

(14) the compound of formula (I) which is a stereochemically purecompound, a salt or hydrate thereof, and a hydrate of the salt;

(15) the above compound in which R¹¹ is a cyclopropyl group having ahalogen atom as a substituent, a salt or hydrate thereof, and a hydrateof the salt;

(16) the above compound in which the cyclopropyl group having a halogenatom as a substituent is a 1,2-cis-halogenocyclopropyl group, a salt orhydrate thereof, and a hydrate of the salt;

(17) the above compound in which the cyclopropyl group having a halogenatom as a substituent is a stereochemically pure substituent, a salt orhydrate thereof, and a hydrate of the salt;

(18) the above compound in which the cyclopropyl group having a halogenatom as a substituent is a (1R,2S)-2-halogenocyclopropyl group, a saltor hydrate thereof, and a hydrate of the salt;

(19) the above compound in which the halogen atom of the cyclopropylgroup having a halogen atom as a substituent is a fluorine atom, a saltor hydrate thereof, and a hydrate of the salt;

(20) the above compound in which each of R³, R⁴, R⁵, R⁶, and R⁷ is ahydrogen atom, a salt or hydrate thereof, and a hydrate of the salt;

(21) the above compound in which n is 1, a salt or hydrate thereof, anda hydrate of the salt;

(22) the compound of formula (I), wherein X¹ is a partial structurerepresented by formula:

 wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; and m is an integer 1 or 2,

 a salt or hydrate thereof, and a hydrate of the salt;

(23) the above compound in which R⁸ and R⁹ are each a hydrogen atom, asalt or hydrate thereof, and a hydrate of the salt;

(24) the above compound in which R⁸ and R⁹ are each a hydrogen atom; andm is 1, a salt or hydrate thereof, and a hydrate of the salt;

(25) the above compound in which R¹ and R² are each a hydrogen atom, asalt or hydrate thereof, and a hydrate of the salt;

(26) a drug characterized by containing the above-described compound, asalt or hydrate thereof, or a hydrate of the salt as an activeingredient;

(27) an antimicrobial agent characterized by containing theabove-described compound, a salt or hydrate thereof, or a hydrate of thesalt as an active ingredient;

(28) a treating agent for an infectious disease characterized bycontaining the above-described compound, a salt or hydrate thereof, or ahydrate of the salt as an active ingredient;

(29) a method for treating a disease characterized by administering theabove-described compound, a salt or hydrate thereof or a hydrate of thesalt;

(30) a method for treating an infectious disease characterized byadministering the above-described compound, a salt or hydrate thereof ora hydrate of the salt;

(31) a method for producing a drug characterized by compounding theabove-described compound, a salt or hydrate thereof or a hydrate of thesalt as an active ingredient;

(32) a method for producing an antimicrobial agent characterized bycompounding the above-described compound, a salt or hydrate thereof or ahydrate of the salt as an active ingredient;

(33) a method for producing a treating agent for an infectious diseasecharacterized by compounding the above-described compound, a salt orhydrate thereof or a hydrate of the salt as an active ingredient;

(34) use of the above-described compound, a salt or hydrate thereof or ahydrate of the salt for production of a drug;

(35) use of the above-described compound, a salt or hydrate thereof or ahydrate of the salt for production of an antimicrobial agent;

(36) use of the above-described compound, a salt or hydrate thereof or ahydrate of the salt for production of a treating agent for an infectiousdisease;

(37) a compound represented by formula:

 wherein R¹¹¹ represents a hydrogen atom, an alkyl group having 1 to 6carbon atoms, or a protective group for amino group;

R² represents a hydrogen atom or an alkyl group having 1 to 6 carbonatoms;

 in which the alkyl group as R¹¹¹ or R² may have one or moresubstituents selected from the group consisting of a hydroxyl group, ahalogen atom, an alkylthio group having 1 to 6 carbon atoms, and analkoxyl group having 1 to 6 carbon atoms;

R³ represents a hydrogen atom, a hydroxyl group, a halogen atom, acarbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxylgroup having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6carbon atoms, in which the alkyl group may have one or more substituentsselected from the group consisting of a hydroxyl group, a halogen atom,and an alkoxyl group having 1 to 6 carbon atoms; R⁴ and R⁵ eachindependently represents a hydrogen atom, a halogen atom, an alkyl grouphaving 1 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbonatoms, in which the alkyl group may have one or more substituentsselected from the group consisting of a hydroxyl group, a halogen atom,and an alkoxyl group having 1 to 6 carbon atoms;

R⁶ and R⁷ each independently represents a hydrogen atom or an alkylgroup having 1 to 6 carbon atoms;

X¹ represents an oxygen atom, a sulfur atom, a partial structure:

 (wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or2)

 or a partial structure:

(wherein R¹⁰ represents a hydrogen atom, a formyl group, an acyl grouphaving 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbonatoms);

n represents an integer 1 or 2; and

Q′ represents a protective group for amino group, a salt or hydratethereof, and a hydrate of the salt;

(38) the above compound in which the protective group for amino group isa protective group selected from the group consisting of a substitutedor unsubstituted alkoxycarbonyl group, a substituted or unsubstitutedaralkyloxycarbonyl group, a substituted or unsubstituted acyl group, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedaralkyl group, and a silyl group, a salt or hydrate thereof, and ahydrate of the salt;

(39) the above compound in which the protective group for amino group isa protective group selected from the group consisting of at-butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, abenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, ap-nitrobenzyloxycarbonyl group, an acetyl group, a methoxyacetyl group,a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, aformyl group, a benzoyl group, a t-butyl group, a benzyl group, ap-nitrobenzyl group, a p-methoxybenzyl group, a triphenylmethyl group, amethoxymethyl group, a t-butoxymethyl group, a tetrahydropyranyl group,a 2,2,2-trichloroethoxymethyl group, a trimethylsilyl group, anisopropyldimethylsilyl group, a t-butyldimethylsilyl group, atribenzylsilyl group, and a t-butyldiphenylsilyl group, a salt orhydrate thereof, and a hydrate of the salt;

(40) the above compound in which R¹¹¹ and Q′ are not the same protectivegroups, a salt or hydrate thereof, and a hydrate of the salt;

(41) the above compound in which n is 1, a salt or hydrate thereof, anda hydrate of the salt;

(42) the above compound in which each of R², R³, R⁴, R⁵, R⁶, and R⁷ is ahydrogen atom, a salt or hydrate thereof, and a hydrate of the salt;

(43) the above compound in which X¹ is a partial structure of formula:

 wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or2,

 a salt or hydrate thereof, and a hydrate of the salt;

(44) the above compound in which m is 1, a salt or hydrate thereof, anda hydrate of the salt;

(45) a compound represented by formula:

 wherein R¹¹¹ represents a hydrogen atom, an alkyl group having 1 to 6carbon atoms, or a protective group for amino group;

R² represents a hydrogen atom or an alkyl group having 1 to 6 carbonatoms;

 in which the alkyl group as R¹¹¹ or R² may have one or moresubstituents selected from the group consisting of a hydroxyl group, ahalogen atom, an alkylthio group having 1 to 6 carbon atoms, and analkoxyl group having 1 to 6 carbon atoms;

R³ represents a hydrogen atom, a hydroxyl group, a halogen atom, acarbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxylgroup having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6carbon atoms, in which the alkyl group may have one or more substituentsselected from the group consisting of a hydroxyl group, a halogen atom,and an alkoxyl group having 1 to 6 carbon atoms;

R⁴ and R⁵ each independently represents a hydrogen atom, a halogen atom,an alkyl group having 1 to 6 carbon atoms, or an alkoxyl group having 1to 6 carbon atoms, in which the alkyl group may have one or moresubstituents selected from the group consisting of a hydroxyl group, ahalogen atom, and an alkoxyl group having 1 to 6 carbon atoms;

R⁶ and R⁷ each independently represents a hydrogen atom or an alkylgroup having 1 to 6 carbon atoms;

X¹ represents an oxygen atom, a sulfur atom, a partial structure:

 (wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or2)

 or a partial structure:

(wherein R¹⁰ represents a hydrogen atom, a formyl group, an acyl grouphaving 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbonatoms); and

n represents an integer 1 or 2,

 a salt or hydrate thereof, and a hydrate of the salt;

(46) the above compound in which the protective group for amino group isa protective group selected from the group consisting of a substitutedor unsubstituted alkoxycarbonyl group, a substituted or unsubstitutedaralkyloxycarbonyl group, a substituted or unsubstituted acyl group, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedaralkyl group, and a silyl group, a salt or hydrate thereof, and ahydrate of the salt;

(47) the above compound in which the protective group for amino group isa protective group selected from the group consisting of at-butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, abenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, ap-nitrobenzyloxycarbonyl group, an acetyl group, a methoxyacetyl group,a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, aformyl group, a benzoyl group, a t-butyl group, a benzyl group, ap-nitrobenzyl group, a p-methoxybenzyl group, a triphenylmethyl group, amethoxymethyl group, a t-butoxymethyl group, a tetrahydropyranyl group,a 2,2,2-trichloroethoxymethyl group, a trimethylsilyl group, anisopropyldimethylsilyl group, a t-butyldimethylsilyl group, atribenzylsilyl group, and a t-butyldiphenylsilyl group, a salt orhydrate thereof, and a hydrate of the salt;

(48) the above compound in which n is 1, a salt or hydrate thereof, anda hydrate of the salt;

(49) the above compound in which each of R², R³, R⁴, R⁵, R⁶, and R⁷ is ahydrogen atom, a salt or hydrate thereof, and a hydrate of the salt;

(50) the above compound in which X¹ is a partial structure of formula:

 wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or2,

 a salt or hydrate thereof, and a hydrate of the salt;

(51) the above compound in which m is 1, a salt or hydrate thereof, anda hydrate of the salt;

(52) a process for preparing a quinolone compound characterized bycomprising removing Q′ from a compound of the following formula, a saltor hydrate thereof, or a hydrate of the salt:

 wherein R¹¹¹ represents a hydrogen atom, an alkyl group having 1 to 6carbon atoms, or a protective group for amino group;

R² represents a hydrogen atom or an alkyl group having 1 to 6 carbonatoms; in which the alkyl group as R¹¹¹ or R² may have one or moresubstituents selected from the group consisting of a hydroxyl group, ahalogen atom, an alkylthio group having 1 to 6 carbon atoms, and analkoxyl group having 1 to 6 carbon atoms;

R³ represents a hydrogen atom, a hydroxyl group, a halogen atom, acarbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxylgroup having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6carbon atoms, in which the alkyl group may have one or more substituentsselected from the group consisting of a hydroxyl group, a halogen atom,and an alkoxyl group having 1 to 6 carbon atoms;

R⁴ and R⁵ each independently represents a hydrogen atom, a halogen atom,an alkyl group having 1 to 6 carbon atoms, or an alkoxyl group having 1to 6 carbon atoms, in which the alkyl group may have one or moresubstituents selected from the group consisting of a hydroxyl group, ahalogen atom, and an alkoxyl group having 1 to 6 carbon atoms;

R⁶ and R⁷ each independently represents a hydrogen atom or an alkylgroup having 1 to 6 carbon atoms;

X¹ represents an oxygen atom, a sulfur atom, a partial structure:

 (wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or2)

 or a partial structure:

(wherein R¹⁰ represents a hydrogen atom, a formyl group, an acyl grouphaving 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbonatoms);

n represents an integer 1 or 2; and

Q′ represents a protective group for amino group, and reacting theresulting compound as obtained or, if desired, as isolated and purifiedwith a compound represented by formula (III):

 wherein X² represents a halogen atom or a hydrogen atom;

X⁴ represents a fluorine atom, a chlorine atom, a bromine atom, asubstituted or unsubstituted phenylsulfonyl group or a substituted orunsubstituted alkylsulfonyl group having 1 to 3 carbon atoms;

Y¹ represents a hydrogen atom, a phenyl group, an acetoxymethyl group, apivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, adimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group,an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having2 to 7 carbon atoms, a phenylalkyl group composed of an alkylene grouphaving 1 to 6 carbon atoms and a phenyl group, or a boron-containinggroup represented by formula (IV):

—B(Y¹¹)Y¹²  (IV)

 (wherein Y¹¹ and Y¹² each represents a fluorine atom or analkylcarbonyloxy group having 2 to 4 carbon atoms);

R¹¹ represents an alkyl group having 1 to 6 carbon atoms, an alkenylgroup having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6carbon atoms, a substituted or unsubstituted cycloalkyl group having 3to 6 carbon atoms, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, an alkoxyl group having 1to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms;

R¹² represents a hydrogen atom or an alkylthio group having 1 to 6carbon atoms;

R¹² and R¹¹ may be taken together with part of the mother skeleton towhich they are bonded to form a cyclic structure that may contain asulfur atom as a ring-constituting atom and an alkyl group having 1 to 6carbon atoms as a substituent;

R¹³ represents a hydrogen atom, an amino group, a hydroxyl group, athiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbonatoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl grouphaving 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbonatoms, in which the amino group may have one or two substituentsselected from the group consisting of a formyl group, an alkyl grouphaving 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbonatoms; and

A¹ represents a nitrogen atom or a partial structure represented byformula (II):

 (wherein X³ represents a hydrogen atom, an amino group, a halogen atom,a cyano group, a halogenomethyl group, a halogenomethoxyl group, analkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxylgroup having 1 to 6 carbon atoms, in which the amino group may have oneor two substituents selected from the group consisting of a formylgroup, an alkyl group having 1 to 6 carbon atoms and an acyl grouphaving 2 to 5 carbon atoms; and X³ and R¹¹ may be taken together withpart of the mother skeleton to which they are bonded to form a cyclicstructure that may contain an oxygen atom, a nitrogen atom or a sulfuratom as a ring-constituting atom and an alkyl group having 1 to 6 carbonatoms as a substituent),

 or a compound represented by formula (V):

wherein X², X⁴, R¹¹, R¹², R¹³, A¹, and Y are as defined above, in thepresence of a base, and if desired removing a protective group;

(53) a process for preparing a quinolone compound characterized bycomprising reacting a compound represented by formula (VI), a salt orhydrate thereof, or a hydrate of the salt:

 wherein R¹¹¹ represents a hydrogen atom, an alkyl group having 1 to 6carbon atoms or a protective group for amino group;

R² represents a hydrogen atom or an alkyl group having 1 to 6 carbonatoms;

 in which the alkyl group as R¹¹¹ or R²may have one or more substituentsselected from the group consisting of a hydroxyl group, a halogen atom,an alkylthio group having 1 to 6 carbon atoms, and an alkoxyl grouphaving 1 to 6 carbon atoms;

R³ represents a hydrogen atom, a hydroxyl group, a halogen atom, acarbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxylgroup having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6carbon atoms, in which the alkyl group may have one or more substituentsselected from the group consisting of a hydroxyl group, a halogen atom,and an alkoxyl group having 1 to 6 carbon atoms;

R⁴ and R⁵ each independently represents a hydrogen atom, a halogen atom,an alkyl group having 1 to 6 carbon atoms, or an alkoxyl group having 1to 6 carbon atoms, in which the alkyl group may have one or moresubstituents selected from the group consisting of a hydroxyl group, ahalogen atom, and an alkoxyl group having 1 to 6 carbon atoms;

R⁶ and R⁷ each independently represents a hydrogen atom or an alkylgroup having 1 to 6 carbon atoms;

X¹ represents an oxygen atom, a sulfur atom, a partial structure:

 (wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or2)

 or a partial structure:

(wherein R¹⁰ represents a hydrogen atom, a formyl group, an acyl grouphaving 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbonatoms); and

n represents an integer 1 or 2,

with a compound represented by formula (III):

 wherein X² represents a halogen atom or a hydrogen atom;

X⁴ represents a fluorine atom, a chlorine atom, a bromine atom, asubstituted or unsubstituted phenylsulfonyl group or a substituted orunsubstituted alkylsulfonyl group having 1 to 3 carbon atoms;

Y¹ represents a hydrogen atom, a phenyl group, an acetoxymethyl group, apivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, adimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group,an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having2 to 7 carbon atoms, a phenylalkyl group composed of an alkylene grouphaving 1 to 6 carbon atoms and a phenyl group, or a boron-containinggroup represented by formula (IV):

 —B(Y¹¹)Y¹²  (IV)

 (wherein Y¹¹ and Y¹² each represents a fluorine atom or analkylcarbonyloxy group having 2 to 4 carbon atoms);

R¹¹ represents an alkyl group having 1 to 6 carbon atoms, an alkenylgroup having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6carbon atoms, a substituted or unsubstituted cycloalkyl group having 3to 6 carbon atoms, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, an alkoxyl group having 1to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms;

R¹² represents a hydrogen atom or an alkylthio group having 1 to 6carbon atoms;

R¹² and R¹¹ may be taken together with part of the mother skeleton towhich they are bonded to form a cyclic structure that may contain asulfur atom as a ring-constituting atom and an alkyl group having 1 to 6carbon atoms as a substituent;

R¹³ represents a hydrogen atom, an amino group, a hydroxyl group, athiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbonatoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl grouphaving 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbonatoms, in which the amino group may have one or two substituentsselected from the group consisting of a formyl group, an alkyl grouphaving 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbonatoms; and

A¹ represents a nitrogen atom or a partial structure represented byformula (II):

 (wherein X³ represents a hydrogen atom, an amino group, a halogen atom,a cyano group, a halogenomethyl group, a halogenomethoxyl group, analkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxylgroup having 1 to 6 carbon atoms, in which the amino group may have oneor two substituents selected from the group consisting of a formylgroup, an alkyl group having 1 to 6 carbon atoms and an acyl grouphaving 2 to 5 carbon atoms;

and X³ and R¹¹ may be taken together with part of the mother skeleton towhich they are bonded to form a cyclic structure that may contain anoxygen atom, a nitrogen atom or a sulfur atom as a ring-constitutingatom and an alkyl group having 1 to 6 carbon atoms as a substituent),

or a compound represented by formula (V):

 wherein X², X⁴, R¹¹, R¹², R¹³, A¹, and Y are as defined above, in thepresence of a base, and if desired removing a protective group; and thelike.

The compound represented by formula (I) according to the presentinvention is described with reference to the substituents thereof.

Substituents R¹ and R² each independently represents a hydrogen atom oran alkyl group having 1 to 6 carbon atoms which may be substituted withone or more substituents selected from the group consisting of ahydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbonatoms, and an alkoxyl group having 1 to 6 carbon atoms.

The alkyl group can be a straight-chain or branched alkyl group having 1to 6 carbon atoms and preferably includes a methyl group, an ethylgroup, an n-propyl group, and an isopropyl group.

Where the alkyl group has a hydroxyl group as a substituent, the alkylgroup having 1 to 6 carbon atoms can be either straight or branched, andthe hydroxyl group is preferably on the terminal carbon atom of thealkyl group. The hydroxyl-substituted alkyl group preferably contains upto 3 carbon atoms and preferably includes a hydroxymethyl group, a2-hydroxyethyl group, a 2-hydroxypropyl group, and a 3-hydroxypropylgroup.

Where the alkyl group has a halogen atom as a substituent, the alkylgroup having 1 to 6 carbon atoms can be either straight or branched, andthe halogen atom is preferably a fluorine atom. The number of fluorinesubstitution is any of from mono-substitution up toperfluoro-substitution. Examples of the halogen-substituted alkyl groupare a monofluoromethyl group, a difluoromethyl group, a trifluoromethylgroup, and a 2,2,2-trifluoroethyl group.

Where the alkyl group has an alkylthio group as a substituent, the alkylgroup having 1 to 6 carbon atoms can be either straight or branched, andthe alkylthio group can be a straight-chain or branched group having 1to 6 carbon atoms. The alkylthio-substituted alkyl group preferablyincludes an alkylthiomethyl group, an alkylthioethyl group, and analkylthiopropyl group, in which the alkylthio group preferably has up to3 carbon atoms. Still preferred are a methylthiomethyl group, anethylthiomethyl group, and a methylthioethyl group.

Where the alkyl group has an alkoxyl group as a substituent, the alkylgroup having 1 to 6 carbon atoms can be either straight or branched, andthe alkoxyl group can be a straight-chain or branched group having 1 to6 carbon atoms. The alkoxy-substituted alkyl group preferably includesan alkoxymethyl group, an alkoxyethyl group, and an alkoxypropyl group,in which the alkoxyl group preferably contains up to 3 carbon atoms.Still preferred are a methoxymethyl group, an ethoxymethyl group, and amethoxyethyl group.

Substituent R³ represents a hydrogen atom, a hydroxyl group, a halogenatom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, analkoxyl group having 1 to 6 carbon atoms, or an alkylthio group having 1to 6 carbon atoms. The alkyl group may have one or more substituentsselected from the group consisting of a hydroxyl group, a halogen atom,and an alkoxyl group having 1 to 6 carbon atoms.

The halogen atom is preferably a fluorine atom or a chlorine atom.

The alkyl group having 1 to 6 carbon atoms can be either straight orbranched and preferably includes a methyl group, an ethyl group, ann-propyl group, and an isopropyl group.

The alkoxyl group having 1 to 6 carbon atoms can be either straight orbranched and preferably includes a methoxyl group and an ethoxy group.

The alkylthio group having 1 to 6 carbon atoms can be either straight orbranched and preferably includes a methylthio group and an ethylthiogroup.

Where a hydroxyl group is on the alkyl group having 1 to 6 carbon atomsas a substituent, the alkyl group can be either straight or branched,and the hydroxyl group is preferably on the terminal carbon atom of thealkyl group. The hydroxyl-substituted alkyl group having 1 to 6 carbonatoms preferably includes a hydroxymethyl group, a 2-hydroxyethyl group,and a 3-hydroxypropyl group.

The halogen atom of the halogen-substituted alkyl group is preferably afluorine atom or a chlorine atom, with a fluorine atom beingparticularly preferred. The alkyl group can be either straight orbranched.

Either alkyl moiety of the alkoxy-substituted alkyl group having 1 to 6carbon atoms can be straight or branched. An alkoxymethyl group or analkoxyethyl group is preferred. Still preferred are a methoxymethylgroup, an ethoxymethyl group, and a 2-methoxyethyl group.

Substituents R⁴ and R⁵ each independently represents a hydrogen atom, ahalogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxylgroup having 1 to 6 carbon atoms, in which the alkyl group can have oneor more substituents selected from the group consisting of a hydroxylgroup, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms.

The halogen atom is preferably a fluorine atom or a chlorine atom.

The alkyl group having 1 to 6 carbon atoms can be either straight orbranched and preferably includes a methyl group, an ethyl group, ann-propyl group, and an isopropyl group.

The alkoxyl group having 1 to 6 carbon atoms can be either straight orbranched and preferably includes a methoxyl group and an ethoxy group.

The hydroxyl-substituted alkyl group having 1 to 6 carbon atoms can beeither straight or branched, and the hydroxyl group is preferably on theterminal carbon atom of the alkyl group. The hydroxyl-substituted alkylgroup having 1 to 6 carbon atoms preferably includes a hydroxymethylgroup, a 2-hydroxyethyl group, and a 3-hydroxypropyl group.

The halogen atom of the halogen-substituted alkyl group is preferably afluorine atom or a chlorine atom, with a fluorine atom beingparticularly preferred. The alkyl group can be either straight orbranched.

Either alkyl moiety of the alkoxy-substituted alkyl group having 1 to 6carbon atoms can be straight or branched. An alkoxymethyl group or analkoxyethyl group is preferred. Still preferred are a methoxymethylgroup, an ethoxymethyl group, and a 2-methoxyethyl group.

Substituents R⁶ and R⁷ each independently represents a hydrogen atom oran alkyl group having 1 to 6 carbon atoms. The alkyl group having 1 to 6carbon atoms can be straight or branched and preferably includes amethyl group, an ethyl group, an n-propyl group, and an isopropyl group.

X¹ represents an oxygen atom, a sulfur atom, a partial structure:

wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or2,

or a partial structure:

 wherein R¹⁰ represents a hydrogen atom, a formyl group, an acyl grouphaving 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbon atoms.

X¹ is preferably the partial structure:

wherein R⁸, R⁹, and m are as defined above.

R⁸ and R⁹ are preferably a hydrogen atom, and m is preferably

n is preferably an integer 1 or 2, still preferably 1.

Q represents a partial structure represented by formula:

In the above formula, A² and A³ each represents a nitrogen atom or acarbon atoms provided that A², A³ and the carbon atom to which they arebonded are linked to form a partial structure:

>C═C(A¹═)—N(R¹¹)—

or a partial structure:

>N—C(A¹═)═C(R¹¹)—.

Q preferably represents a condensed heterocyclic structure representedby formula:

or formula:

Substituent R¹¹ represents an alkyl group having 1 to 6 carbon atoms, analkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1to 6 carbon atoms, a substituted or unsubstituted cycloalkyl grouphaving 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, an alkoxyl group having 1to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms.

The alkyl group having 1 to 6 carbon atoms is particularly preferably anethyl group. The alkenyl group having 2 to 6 carbon atoms preferablyincludes a vinyl group and a 1-isopropenyl group. The halogenoalkylgroup having 1 to 6 carbon atoms is preferably a 2-fluoroethyl group.The cycloalkyl group is preferably a cyclopropyl group. The substituenton the cycloalkyl group is preferably a halogen atom, which ispreferably a fluorine atom.

The substituted or unsubstituted aryl group includes a phenyl groupwhich may have 1 to 3 substituents selected from the group consisting ofa halogen atom (e.g., fluorine, chlorine, and bromine), a hydroxylgroup, an amino group, a nitro group, an alkyl group having 1 to 6carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, etc. Thesubstituted or unsubstituted aryl group preferably includes a phenylgroup, a 2-fluorophenyl group, a 4-fluorophenyl group,2,4-difluorophenyl group, and a 2-fluoro-4-hydroxyphenyl group.

The heteroaryl group is a substituent derived from a 5-membered or6-membered aromatic heterocyclic compound containing at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom andincludes a pyridyl group and a pyrimidyl group. The substituents on theheteroaryl group preferably include an alkyl group and a halogen atom.

The alkoxyl group having 1 to 6 carbon atoms is preferably a methoxylgroup. The alkylamino group having 1 to 6 carbon atoms is preferably amethylamino group.

Substituent R¹¹ is preferably a cycloalkyl group or a halogenocycloalkylgroup, still preferably a cyclopropyl group or a 2-halogenocyclopropylgroup, in which the halogen atom is preferably a fluorine atom.

Substituent R¹² represents a hydrogen atom or an alkylthio group having1 to 6 carbon atoms, or R¹¹ and R¹² may be taken together with part ofthe mother skeleton (that is, the nitrogen atom to which R¹¹ is bondedand the carbon atom to which R¹² is bonded) to form a hydrocarbon ringstructure. The ring formed may contain a sulfur atom in its ring. Thering may be substituted with an alkyl group having 1 to 6 carbon atoms.The ring can be a 4- to 6-membered ring and may be saturated, partiallysaturated or unsaturated. The condensed ring structure thus formedincludes the following structures.

Substituent X² represents a halogen atom or a hydrogen atom. The halogenatom is preferably a fluorine atom. X² is preferably a fluorine atom ora hydrogen atom.

Substituent R¹³ represents a hydrogen atom, an amino group, a hydroxylgroup, a thiol group, a halogenomethyl group, an alkyl group having 1 to6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynylgroup having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6carbon atoms, in which the amino group may have one or two substituentsselected from the group consisting of a formyl group, an alkyl grouphaving 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbonatoms.

The alkyl group having 1 to 6 carbon atoms can be straight or branchedand preferably includes a methyl group, an ethyl group, an n-propylgroup, and an isopropyl group. The alkenyl group having 2 to 6 carbonatoms can be straight or branched and preferably includes a vinyl group.The alkynyl group having 2 to 6 carbon atoms can be straight or branchedand preferably includes an ethynyl group. The halogen of thehalogenomethyl group is preferably a fluorine atom. The halogenomethylgroup can have 1 to 3 halogen atoms. The alkoxyl group can have 1 to 6carbon atoms and is preferably a methoxyl group.

Substituent R¹³ is preferably a hydrogen atom, an alkyl group or anamino group, with a methyl group or an unsubstituted amino group beingstill preferred.

Where substituent R¹³ is an amino group, a hydroxyl group or a thiolgroup, it may be protected with a commonly employed protective group.

Specific examples of the protective group include (substituted)alkoxycarbonyl groups, e.g., a t-butoxycarbonyl group and a2,2,2-trichloroethoxycarbonyl group; (substituted) aralkyloxycarbonylgroups, e.g., a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonylgroup, and a p-nitrobenzyloxycarbonyl group; (substituted) acyl groups,e.g., an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, achloroacetyl group, a pivaloyl group, a formyl group, and a benzoylgroup; (substituted) alkyl groups or (substituted) aralkyl groups, e.g.,a t-butyl group, a benzyl group, a p-nitrobenzyl group, ap-methoxybenzyl group, and a triphenylmethyl group; (substituted) ethergroups, e.g, a methoxymethyl group, a t-butoxymethyl group, atetrahydropyranyl group, and a 2,2, 2-trichloroethoxymethyl group; and(alkyl- and/or aralkyl)-substituted silyl groups, e.g., a trimethylsilylgroup, an isopropyldimethylsilyl group, a t-butyldimethylsilyl group, atribenzylsilyl group, and a t-butyldiphenylsilyl group. The term“substituted” in parentheses as used above means substituted orunsubstituted (hereinafter the same). The compounds having the thusprotected substituent are particularly useful as an intermediate forsynthesis.

Where A¹ is a partial structure of formula (II):

X³ represents a hydrogen atom, an amino group, a halogen atom, a cyanogroup, a halogenomethyl group, a halogenomethoxyl group, an alkyl grouphaving 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms,an alkynyl group having 2 to 6 carbon atoms, or an alkoxyl group having1 to 6 carbon atoms, in which the amino group can have one or twosubstituents selected from the group consisting of a formyl group, analkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5carbon atoms.

The alkyl group can be a straight-chain or branched alkyl group having 1to 6 carbon atoms and preferably includes a methyl group, an ethylgroup, an n-propyl group, and an isopropyl group. The alkenyl group canbe a straight-chain or branched alkenyl group having 2 to 6 carbon atomsand preferably includes a vinyl group. The alkynyl group can be astraight-chain or branched alkenyl group having 2 to 6 carbon atoms andpreferably includes an ethynyl group. The halogenomethyl group cancontain 1 to 3 halogen atoms, and the halogen atom thereof is preferablya fluorine atom. The alkoxyl group has 1 to 6 carbon atoms and ispreferably a methoxyl group. The halogenomethoxyl group can have 1 to 3halogen atoms, and the halogen atom thereof is preferably a fluorineatom.

Of these substituents an alkyl group and an alkoxyl group are preferred.A methyl group and an ethyl group are still preferred. They arepreferred particularly where Q is a partial structure of formula:

X³ and R¹¹ may be taken together with part of the mother skeleton (thatis, so as to include the carbon atom to which X³ is bonded and thenitrogen atom to which R¹¹ is bonded) to form a hydrocarbon ringstructure. The ring has a size of from 4- to 6-membered rings and may besaturated, partially saturated or unsaturated. The ring may contain anoxygen atom, a nitrogen atom or a sulfur atom as a ring-constitutingatom. The ring may also have an alkyl group having 1 to 6 carbon atomsas a substituent. The condensed ring structure thus formed includes thefollowing structures.

Of the condensed rings preferred is a2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-6-carboxylicacid-10-yl group, especially the 3(S)-methyl form thereof.

Q preferably represents a partial structure of formula:

Q still preferably represents the above structure in which A¹ is thepartial structure of formula (II).

Where Q is the partial structure shown above in which A¹ is the partialstructure of formula (II), R¹³ and X³ are preferably selected to makesuch a combination that R¹² is an amino group, a hydrogen atom, ahydroxyl group or an alkyl group having 1 to 6 carbon atoms, and X³ isan alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to6 carbon atoms, a halogenomethoxyl group or a hydrogen atom. In a stillpreferred combination, R¹³ is an amino group, a hydrogen atom, ahydroxyl group or a methyl group, and X³ is a methyl group, a methoxylgroup, a difluoromethoxyl group or a hydrogen atom. A particularlypreferred combination is that R¹³ is an amino group, a hydrogen atom, ahydroxyl group or a methyl group, and X³ is a methyl group or a methoxylgroup.

In the above cases, X² is preferably a fluorine atom.

Where X² and X³ are each a halogen atom, X² is preferably a fluorineatom, and X³ is preferably a fluorine atom or a chlorine atom.

Where Q is a partial structure represented by formula:

and A¹ is the partial structure of formula (II), R¹³ and X³ arepreferably selected to make such a combination that R¹² is an aminogroup, a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 6carbon atoms, and X³ is an alkyl group having 1 to 6 carbon atoms, analkoxyl group having 1 to 6 carbon atoms, a halogenomethoxyl group or ahydrogen atom. In a still preferred combination, R¹³ is an amino group,a hydrogen atom, a hydroxyl group or a methyl group, and X³ is a methylgroup, a methoxyl group, a fluorine atom, a chlorine atom, adifluoromethoxyl group or a hydrogen atom. A particularly preferredcombination is that R¹³ is an amino group, a hydrogen atom, a hydroxylgroup or a methyl group, and X³ is a methyl group or a methoxyl group.

Where X² and X³ are each a halogen atom, X² is preferably a fluorineatom, and X³ is preferably a fluorine atom or a chlorine atom.

The halogenocyclopropyl group as R¹¹ will hereinafter be described.

The substituent halogen atom includes a fluorine atom and a chlorineatom, with a fluorine atom being preferred.

It is particularly preferred that the halogen atom and thepyridonecarboxylic acid moiety be in a cis-configuration with respect tothe cyclopropane ring.

The cis-2-halogenocyclopropyl moiety as R¹¹ makes a pair of antipodes byitself, each of which was observed to exhibit potent antimicrobialactivity and high safety.

The compound of the present invention is characterized by having thesubstituent represented by the following structure:

In this substituent, it is usual that the substituents −N(R¹)R² and R³are in a cis-configuration, so are the substituents R⁴ and R⁵. Thereforethere are 4 isomers with respect to the condensed rings on which thesesubstituents are.

Where the compound of formula (I) of the invention has such a structurethat produces diastereomers, it is desirable to administer a compoundcomprising a pure diastereomer in administration to humans or animals.The language “a compound comprising a pure diastereomer” as used hereinis construed as including not only a compound containing no otherdiastereomers at all but a compound containing other diastereomers tosuch an extent that the compound is regarded to be chemically pure. Inother words, it is construed as meaning that other diastereomers mayexist to some extent as long as the existence gives no substantialinfluence on physical constants or physiological activities.

The language “stereochemically pure” as used herein is intended to meanthat a compound comprises only one of its stereoisomers ascribed to itsasymmetric carbon atom. The latitude of the term “pure” in “purediastereomer” also applies here.

The pyridonecarboxylic acid derivative of the present invention may haveeither a free form or a form of an acid addition salt or a carboxylicacid salt. Acid addition salts include inorganic acid salts, such as ahydrochloride, a sulfate, a nitrate, a hydrobromide, a hydroiodide, anda phosphate; and organic acid salts, such as an acetate, ametanesulfonate, a benzenesulfonate, a toluenesulfonate, a citrate, amaleate, a fumarate, and a lactate.

The carboxylic acid salts include inorganic salts and organic salts,such as alkali metal salts, e.g., a lithium salt, a sodium salt, and apotassium salt; alkaline earth metal salts, e.g., a magnesium salt and acalcium salt; an ammonium salt; a triethylamine salt, anN-methylglucamine salt, and a tris-(hydroxymethyl)aminomethane salt.

The free pyridonecarboxylic acid derivatives, acid addition saltsthereof, and carboxylic acid salts thereof may be present as a hydrate.

On the other hand, quinolone derivatives with the carboxylic acid moietythereof having an ester form are useful as an intermediate for synthesisor a pro-drug. For example, alkyl esters, benzyl esters, alkoxyalkylesters, phenylalkyl esters, and phenyl esters are useful asintermediates for synthesis.

Esters which can be used as pro-drugs are those which are susceptible toan in vivo cleavage to form a free carboxylic acid, including anacetoxymethyl ester, a pivaloyloxymethyl ester, an ethoxycarbonyl ester,a choline ester, a dimethylaminoethyl ester, a 5-indanyl ester, aphthalidinyl ester, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester, andoxoalkyl esters, such as a 3-acetoxy-2-oxobutyl ester.

The compound of formula (I) can be prepared through various processes. Apreferred process comprises reacting a compound represented by formula(III):

wherein X⁴ represents a group functioning as a leaving group, such as afluorine atom, a chlorine atom, a bromine atom, a substituted orunsubstituted phenylsulfonyl group, a substituted or unsubstitutedalkylsulfonyl group having 1 to 3 carbon atoms, and the like;

Y¹ has the same meaning as Y in formula (I) or represents aboron-containing group represented by formula (IV):

−B(y¹¹)Y¹²  (IV)

 (wherein Y¹¹ and Y¹² each represent a fluorine atom or analkylcarbonyloxy group having 2 to 4 carbon atoms); and

R¹¹, R¹², R¹³, A¹, and X² are as defined in formula (I), or a compoundrepresented by formula (V):

 wherein X⁴ represents a group functioning as a leaving group, such as afluorine atom, a chlorine atom, a bromine atom, a substituted orunsubstituted phenylsulfonyl group, a substituted or unsubstitutedalkylsulfonyl group having 1 to 3 carbon atoms, and the like; and R¹¹,R¹², R¹³, A¹, X², and Y are as defined in formula (I),

 with a compound represented by formula (VI):

 wherein R¹¹¹ has the same meaning as R¹ in formula (I) or represents aprotective group for amino group; and R², R³, R⁴, R⁵, R⁶, R⁷, X¹, and nare as defined in formula (I), or an acid addition salt thereof.

The reaction is carried out with or without a solvent. The solvent whichcan be used in the reaction is not limited as long as it is inert underthe reaction conditions. Suitable solvents include dimethyl sulfoxide,pyridine, acetonitrile, ethanol, chloroform, dimethylformamide,dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, water, and3-methoxybutanol, and mixtures thereof.

It is advantageous to conduct the reaction in the presence of an acidacceptor, such as an inorganic base (e.g., an alkali metal or alkalineearth metal carbonate or hydrogencarbonate) or an organic base (e.g.,triethylamine, pyridine or 1,8-diazabicycloundecene). The reaction isusually performed at room temperature to 200° C., preferably 25 to 150°C., for 0.5 to 48 hours. The reaction usually completes in about 0.5 to2 hours.

Any protective group generally used in the art can be used as aprotective group for amino group. Examples of useful protective groupsinclude (substituted) alkoxycarbonyl groups, e.g., a t-butoxycarbonylgroup and a 2,2,2-trichloroethoxycarbonyl group; (substituted)aralkyloxycarbonyl groups, e.g., a benzyloxycarbonyl group, ap-methoxybenzyloxycarbonyl group, and a p-nitrobenzyloxycarbonyl group;(substituted) acyl groups, e.g., an acetyl group, a methoxyacetyl group,a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, aformyl group, and a benzoyl group; (substituted) alkyl groups or(substituted) aralkyl groups, e.g., a t-butyl group, a benzyl group, ap-nitrobenzyl group, a p-methoxybenzyl group, and a triphenylmethylgroup; (substituted) ether groups, e.g, a methoxymethyl group, at-butoxymethyl group, a tetrahydropyranyl group, and a2,2,2-trichloroethoxymethyl group; and (alkyl- and/oraralkyl)-substituted silyl groups, e.g., a trimethylsilyl group, anisopropyldimethylsilyl group, a t-butyldimethylsilyl group, atribenzylsilyl group, and a t-butyldiphenylsilyl group.

The resulting compound in which Y or y¹ is an alkyl group having 1 to 6carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or aphenylalkyl group composed of an alkylene group having 1 to 6 carbonatoms and a phenyl group can be converted to the correspondingcarboxylic acid by treating under an acidic or basic condition commonlyused for hydrolysis of carboxylic acid esters.

Where y¹ is the structure of formula (IV), the compound obtained by thereaction between the compound (III) or the compound (V) and the compound(VI) can be converted to the corresponding carboxylic acid by treatingunder an acidic or basic condition.

When removal of a protective group is necessary, the protective group isremoved under the condition properly selected for that protective groupto give a desired compound represented by formula (I).

The compound of formula (VI) can be prepared by various processes. Apreferred process is shown in Reference Examples hereinafter given, butthe process is not limited thereto. The compound of formula (VI) isprepared by removing Q′ from a compound represented by formula:

wherein R¹¹¹ is the same as R¹ as defined in formula (I) or represents aprotective group for amino group; R², R³, R⁴, R⁵, R⁶, R⁷, X¹, and n areas defined in formula (I); and Q′ is a protective group for amino group,which can be selected from the group consisting of a (substituted)alkoxycarbonyl group, a (substituted) aralkyloxycarbonyl group, a(substituted) acyl group, a (substituted) alkyl group, a (substituted)aralkyl group, and a silyl group.

The above compound can exist in the form of a salt, a hydrate, or ahydrate of the salt. Acid addition salts include inorganic acid saltsand organic acid salts. Examples of the inorganic acid salts are ahydrochloride, a sulfate, a nitrate, a hydrobromide, a hydroiodide, anda phosphate. Examples of the organic acid salts include sulfonates, suchas a metanesulfonate, a benzenesulfonate, and a toluenesulfonate, andcarboxylates, such as an acetate, a citrate, a maleate, a fumarate, anda lactate.

Where both R¹¹¹ and Q′ represent a protective group for amino group,while they may be the same or different, it is advantageous for thepreparation of the compound (I) that these protective groups aredifferent so that they are released under the respective differentreaction conditions.

The protective group for amino group as R¹¹¹ and Q′ includes(substituted) alkoxycarbonyl groups, (substituted) aralkyloxycarbonylgroups, (substituted) acyl groups, (substituted) alkyl groups,(substituted) aralkyl groups, and silyl groups. Specific examples are(substituted) alkoxycarbonyl groups, e.g., a t-butoxycarbonyl group anda 2,2,2-trichloroethoxycarbonyl group; (substituted) aralkyloxycarbonylgroups, e.g., a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonylgroup, and a p-nitrobenzyloxycarbonyl group; (substituted) acyl groups,e.g., an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, achloroacetyl group, a pivaloyl group, a formyl group, and a benzoylgroup; (substituted) alkyl groups or (substituted) aralkyl groups, e.g.,a t-butyl group, a benzyl group, a p-nitrobenzyl group, ap-methoxybenzyl group, and a triphenylmethyl group; ether groups, e.g, amethoxymethyl group, a t-butoxymethyl group, a tetrahydropyranyl group,and a 2,2,2-trichloroethoxymethyl group; and substituted silyl groups,e.g., a trimethylsilyl group, an isopropyldimethylsilyl group, at-butyldimethylsilyl group, a tribenzylsilyl group, and at-butyldiphenylsilyl group.

In order to prepare the compound (I) by using the above-describedcompound having the protective group Q′, it is necessary to remove theprotective group Q′ before reacting. In this case, the compound (VI) asobtained may be either subjected to the reaction with the compound (III)or (V) immediately after the protective group removal, usually in thesame pot, or once isolated and then reacted.

Cis-2-fluorocyclopropylamine comprising a pure isomer, which ispreferred for the synthesis of the compound of formula (I) comprising apure isomer, can be synthesized by, for example, the process describedin JP-A-2-231475. Synthesis of the compound of formula (I) comprising apure isomer from the optically active cis-2-fluorocyclopropylaminederivative thus obtained can be carried out by, for example, the processdescribed in JP-A-2-231475.

Examples of the compounds of the present invention are shown below.10-{(1R,2R,6S)-1-Amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4]benzoxazine-6-carboxylicacid,8-amino-10-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.0^(2, 6)]nonan-4-yl}-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4]benzoxazine-6-carboxylicacid,5-amino-7-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,5-amino-7-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,7-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,7-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,7-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,8-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl∇-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylicacid, and10-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-9-fluoro-3-(S)-methyl-2H,3H,6H-oxopyrano[2,3,4-IJ]quinolizine-5-carboxylicacid.

The structures of these specific compounds are shown below.

The compounds of the present invention have potent antimicrobialactivity and are therefore useful as drugs for humans, animals orfishes, agricultural chemicals, or food preservatives.

For use as drugs for humans, the dose of the compound is in the range offrom 50 mg to 1 g, preferably from 100 mg to 300 mg, per day for anadult.

For veterinary use, the dose is generally in the range of from 1 to 200mg, preferably from 5 to 100 mg, per kg of body weight per day whilevarying depending on the purpose of administration (for therapy or forprevention), the kind and size of the animal, the kind of the pathogenicbacterium and the severity of infection.

The above-mentioned daily dose is given once a day or in 2 to 4 divideddoses per day. If necessary, a daily dose may exceed the above-specifiedupper limit.

The compounds according to the invention are active on a broad range ofmicroorganisms causing various infectious diseases and effective toprevent, alleviate or cure diseases caused by these pathogens.

Examples of bacteria or bacterium-like microorganisms on which thecompounds of the invention are effective include Staphylococcus,Streptococcus pyogenes, hemolytic streptococcus, Enterococcus,Streptococcus pneumoniae, peptostreptococcus, gonococcus, Escherichiacoli, Citrobacter, Shigella, Klebsiella pneumoniae, Enterobacter,Serratia, Proteus, Pseudomonas aeruginosa, Haemophilus influenzae,Acinetobacter, Campylobacter, and Chlamydozoon trachomatis.

Diseases which are caused by these pathogens include folliculitis,furuncle, carbuncle, erysipelas, phlegmon, lymphangitis/lymphadenitis,felon, subcutaneous abscess, spiradenitis, acne agminate, infectiousatheroma, perianal abscess, mastadenitis, superficial secondaryinfections after trauma, burn or surgery trauma, pharyngolaryngitis,acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis,diffuse panbronchiolitis, secondary infections of chronic respiratorydiseases, pneumonia, pyelonephritis, cystitis, prostatitis,epididymitis, gonococcal urethritis, non-gonococcal urethritis,cholecystitis, cholangitis, bacillary dysentery, enteritis, adnexitis,intrauterine infections, bartholinitis, blepharitis, hordeolum,dacryocystitis, tarsadenitis, keratohelcosis, otitis media, sinusitis,paradentosis, pericoronitis, gnathitis, peritonitis, endocarditis,septicemia, meningitis, and skin infections.

The compounds of the invention are also effective on variousmicroorganisms causing veterinary infectious diseases, such as thosebelonging to the genera Escherichia, Salmonella, Pasteurella,Haemophilus, Bordetella, Staphylococcus, and Mycoplasma. Illustrativeexamples of the diseases include those of fowl, such as colibacillosis,pullorum disease, avian paratyphosis, fowl cholera, infectious coryza,staphylomycosis, and mycoplasmosis; those of pigs, such ascolibacillosis, salmonellosis, pasteurellosis, hemophilus infections,atrophic rhinitis, exudative epidermitis, and mycoplasmosis; those ofcattle, such as colibacillosis, salmonellosis, hemorrhagic septicemia,mycoplasmosis, bovine contagious pleuropneumonia, and bovine mastitis;those of dogs, such as colisepsis, salmonellosis, hemorrhagicsepticemia, pyometra, and cystitis; those of cats, such as exudativepleurisy, cystitis, chronic rhinitis, and hemophilus infections; andthose of kittens, such as bacterial diarrhea and mycoplasmosis.

Dosage forms of antimicrobial preparations containing the compound ofthe present invention are appropriately selected according to theadministration route and can be prepared by conventional preparationmethods. Examples of dosage forms for oral administration includetablets, powders, granules, capsules, solutions, syrups, elixirs, andoily or aqueous suspensions.

Injectable preparations may contain adjuvants, such as stabilizers,antiseptics, and solubilizers. The injectable solution which may containthese adjuvants may be put into a container and solidified by, forexample, lyophilization to prepare a solid preparation, which isdissolved on use. The container may contain either a single dose ormultiple doses.

Preparations for external application include solutions, suspensions,emulsions, ointments, gels, creams, lotions, and sprays.

Solid preparations may contain, in addition to the active compound,pharmaceutically acceptable additives. For example, the active compoundis mixed with additives selected according to necessity from amongfillers, extenders, binders, disintegrators, absorption accelerators,wetting agents, and lubricants and formulated into solid preparations.

Liquid preparations include solutions, suspensions, and emulsions. Theymay contain adjuvants, such as suspending agents, emulsifiers, and soforth.

The compound can be administered to animals orally either directly or bymixing into feedstuff, or in a dissolved form directly given to animalsor by mixing into water or feedstuff or non-orally by injection.

For veterinary use, the compound can be formulated into powders, finegranules, soluble powders, syrups, solutions, and injections accordingto the customary methods in the art.

Formulation Examples are shown below.

FORMULATION EXAMPLE 1

Capsules: Compound of Example 3 100.0 mg Corn starch 23.0 mg CMC.Ca 22.5mg Hydroxymethyl cellulose 3.0 mg Magnesium stearate 1.5 mg Total: 150.0mg

FORMULATION EXAMPLE 2

Solution: Compound of Example 2 1 to 10 g Acetic acid or sodiumhydroxide 0.5 to 2 g Ethyl p-hydroxybenzoate 0.1 g Purified water 88.9to 98.4 g Total: 100 g

FORMULATION EXAMPLE 3

Powder for Mixing into Feed: Compound of Example 2 1 to 10 g Corn starch89.5 to 98.5 g Light anhydrous silicic acid 0.5 g Total: 100 g

BEST EMBODIMENTS FOR CARRYING OUT THE INVENTION

The present invention will further be illustrated by way of Examples andReference Examples, but the present invention should not be construed asbeing limited thereto.

REFERENCE EXAMPLE 1

7-Benzyl-2-oxo-7-azabicyclo[3.3.0]octane:

Trifluoroacetic acid (385 μl) was added to a solution of2-cyclopenten-1-one (10.1 ml, 120 mmol) andbenzylbutoxymethyltrimethylsilylmethylamine (41.9 g, 150 mmol) indichloromethane (300 ml) at room temperature, followed by stirring for16 hours. The dichloromethane was evaporated, and a saturated aqueoussolution of sodium hydrogencarbonate was added to the residue. Themixture was extracted with ethyl acetate. The organic layer was washedwith a saturated sodium chloride aqueous solution and dried overanhydrous sodium sulfate. The solvent was evaporated, and the residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to give 24.92 g (115.7 mmol, 96%) of the title compound asa yellow oily substance. ¹H-NMR (400 MHz, CDCl₃) δ: 1.75-1.83 (1H, m),2.08-2.18 (1H, m), 2.24-2.32 (1H, m), 2.37-2.49 (2H, m), 2.59-2.64 (1H,m), 2.67 (1H, dd, J=2.5, 9.5 Hz), 2.85-2.93 (1H, m), 3.04 (1H, dd,J=1.5, 9.5 Hz), 3.48 (1H, d, J=13.0 Hz), 3.61 (1H, d, J=13.0 Hz),7.21-7.31 (5H, m).

REFERENCE EXAMPLE 2

7-Benzyloxycarbonyl-2-oxo-7-azabicyclo[3.3.0]octane:

Benzyloxycarbonyl chloride (5.14 ml, 36.0 mmol) was added dropwise to asolution of 7-benzyl-2-oxo-7-azabicyclo[3.3.0]octane (5.20 g, 24.2 mmol)in dichloromethane (50 ml) under cooling with ice, followed by stirringat room temperature for 24 hours. The mixture was again cooled with ice,and benzyloxycarbonyl chloride (5.14 ml, 36.0 mmol) was added theretodropwise. After removing the solvent by evaporation, the residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to give 4.52 g (17.4 mmol, 72%) of the title compound as acolorless oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 1.80-1.90 (1H, m), 2.12-2.22 (1H, m),2.35-2.39 (2H, m), 2.76 (1H, dt, J=3.5, 8.5 Hz), 3.01-3.11 (1H, m),3.16-3.26 (1H, m), 3.61-3.66 (1H, m), 3.69-3.78 (1H, m), 5.11-5.12 (2H,m), 7.29-7.38 (5H, m).

REFERENCE EXAMPLE 3

2-(N-Benzyl-N-benzyloxycarbonyl)amino-7-benzyloxycarbonyl-7-azabicyclo[3.3.0]oct-2-ene:

Benzylamine (2.08 ml, 19.0 mmol) was added dropwise to a mixture of7-benzyloxycarbonyl-2-oxo-7-azabicyclo[3.3.0]octane (4.51 g, 17.4 mmol),anhydrous magnesium sulfate (3.5 g), and tetrahydrofuran (50 ml) undercooling with ice. After stirring the mixture for 1 hour, the insolublematter was removed by filtration, and the filtrate was concentrated. Theresulting residue was dissolved in benzene (60 ml), and triethylamine(4.88 ml, 35.0 mmol) was added to the solution. To the mixture wasfurther added triphosgene (2.67 g, 9.0 mmol) under cooling with ice,followed by stirring at room temperature for 1 hour. The insolublematter was removed by Celite filtration, and the filtrate wasconcentrated. The residue was dissolved in tetrahydrofuran (30 ml), andthe solution was added dropwise to a tetrahydrofuran (50 ml) solution ofbenzyloxysodium (25.0 mmol) under ice-cooling, followed by stirring atroom temperature for 30 minutes. A saturated ammonium chloride aqueoussolution was added thereto under cooling with ice, and the mixture wasextracted with ethyl acetate. The extract was washed successively withwater and a saturated sodium chloride aqueous solution and dried overanhydrous sodium sulfate. After the solvent was removed by evaporation,the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=1:1) to give 2.22 g (10.3 mmol, 59%) of thetitle compound as a colorless oily substance.

REFERENCE EXAMPLE 4

1-(N-Benzyl-N-benzyloxycarbonyl)amino-4-benzyloxycarbonyl-4-azatricyclo[6.1.0.0_(2,6)]nonane:

Diethylzinc (1 M n-hexane solution; 20 ml, 20.0 mmol) was added to asolution of2-(N-benzyl-N-benzyloxycarbonyl)amino-7-benzyloxycarbonyl-7-azabicyclo[3.3.0]oct-2-ene(920 mg, 1.91 mmol) in dichloromethane (50 ml) at room temperature, anddiiodomethane (3.06 ml, 38.0 mmol) was added thereto dropwise. Afterstirring the mixture for 16 hours, a saturated ammonium chloride aqueoussolution was added thereto, and the mixture was extracted with ethylacetate. The organic layer was washed successively with a sodiumthiosulfate aqueous solution and a saturated sodium chloride aqueoussolution, and dried over anhydrous sodium sulfate. After the solvent wasevaporated, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=3:1) to give 678 mg (1.36 mmol, 71%) of thetitle compound as a colorless oily substance.

REFERENCE EXAMPLE 5

1-Amino-4-azatricyclo[6.1.0.0^(2,6)]nonane:

To a solution of1-(N-benzyl-N-benzyloxycarbonyl)amino-4-benzyloxycarbonyl-4-azatricyclo-[6.1.0.0^(2,6)]nonane(675 mg, 1.36 mmol) in methanol (50 ml) was added 20% palladiumhydroxide-on-carbon (500 mg), and the mixture was vigorously stirred ina hydrogen atmosphere for 120 hours. The insoluble matter was removed byCelite filtration, and the filtrate was concentrated to give the titlecompound as a crude colorless oily substance.

EXAMPLE 1

5-Amino-7-(1-amino-4-azatricyclo[6.1.0.0^(2,6)]-nonan-4-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicAcid:

5-Amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (298 mg, 1.0 mmol) was added to a solution of1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonane (206 mg, 1.36 mmol) andtriethylamine (418 μl, 3.0 mmol) in acetonitrile (10 ml) at roomtemperature, and the mixture was heated under reflux for 16 hours. Aftercooling to room temperature, the acetonitrile was evaporated. To theresidue was added an aqueous hydrochloric acid solution, followed bywashing with chloroform. The aqueous layer was made alkaline with anaqueous sodium hydroxide solution and washed with chloroform. Theaqueous layer was adjusted to pH 7.5 with an aqueous hydrochloric acidsolution and extracted with chloroform. The extract was dried overanhydrous sodium sulfate, and the solvent was removed by evaporation.The residue was recrystallized from ethanol. Recrystallization from2-propanol gave 21 mg of the title compound as yellow crystals.

¹H-NMR (400 MHz, 0.1N-NaOD) δ: 0.06-0.08 (2H, m), 0.30-0.62 (4H, m),0.73-0.75 (1H, m), 1.17-1.21 (1H, m), 1.27-1.36 (1H, m), 1.72-1.77 (1H,m), 2.10-2.17 (1H, m), 2.73-2.77 (1H, m), 3.00-3.08 (1H, m), 3.23-3.31(3H, m), 7.68 (1H, s);

Melting point: 197-202° C. (decomposition);

Elemental analysis for C₂₁H₂₂F₂N₄O₃.5H₂O:

Calcd.: C, 59.28; H, 5.44; N, 13.17

Found: C, 59.48; H, 5.40; N, 12.90

REFERENCE EXAMPLE 6

(1R,5S)-7-Benzyl-2-oxo-7-azabicyclo[3.3.0]oct-3-ene:

Trifluoroacetic acid (154 μl) was added to a solution of(4R)-4-t-butyldimethylsilyloxy-2-cyclopenten-1-one (5.79 g, 27.3 mmol)and benzylbutoxymethyltrimethylsilylmethylamine (15.4 g, 55.0 mmol) indichloromethane (100 ml) at room temperature, followed by stirring for20 minutes. A saturated sodium hydrogencarbonate aqueous solution wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with a saturated sodium chlorideaqueous solution and dried over anhydrous sodium sulfate. After removingthe solvent by evaporation, the residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=1:1) to give 4.21 g (19.7mmol, 72%) of the title compound as a colorless oily substance.(1R,4R,5S)-7-Benzyl-4-t-butyldimethylsilyloxy-2-oxo-7-azabicyclo[3.3.0]octanewas also obtained as a mixture with t-butyldimethylsilanol (3.10 g). Theresulting mixture (3.10 g) of(1R,4R,5S)-7-benzyl-4-t-butyldimethylsilyloxy-2-oxo-7-azabicyclo[3.3.0]octaneand t-butyldimethylsilanol was dissolved in tetrahydrofuran (30 ml), anda 1 M tetrahydrofuran solution (15 ml) of tetrabutylammonium fluoridewas added thereto under cooling with ice, followed by stirring at roomtemperature for 20 minutes. The reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was washed with asaturated sodium chloride aqueous solution and dried over anhydroussodium sulfate. The solvent was removed by evaporation, and the residuewas purified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to give 1.57 g (7.34 mmol) of the title compound as acolorless oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 2.32 (1H, t, J=9.0 Hz), 2.37 (1H, t, J=9.0Hz), 2.72-2.76 (1H, m), 2.78 (1H, d J=9.5 Hz), 3.10 (1H, d, J=9.5 Hz),3.36-3.41 (1H, m), 3.51 (1H, d, J=13.0 Hz), 3.60 (1H, d, J=13.0 Hz),6.24 (1H, dd, J=1.0, 5.5 Hz), 7.20-7.30 (5H, m), 7.56 (1H, dd, J=2.5,5.5 Hz).

(1R,4R,5S)-7-Benzyl-4-t-butyldimethylsilyloxy-2-oxo-7-azabicyclo[3.3.0]octane:

¹H-NMR (400 MHz; CDCl₃) δ: −0.01 (3H, s), 0.00 (3H, s), 0.81 (9H, s),2.23 (1H, ddt, J=1.5, 3.0, 17.0 Hz), 2.33-2.38 (2H, m), 2.57 (1H, dd,J=5.5, 17.0 Hz), 2.71-2.75 (3H, m), 3.04 (1H, d, J=9.0 Hz), 3.39 (1H, d,J=13.0 Hz), 3.60 (1H, d, J=13.0 Hz), 4.18-4.20 (1H, m), 7.18-7.27 (5H,m)

REFERENCE EXAMPLE 7

(1R,5S)-7-Benzyl-2-oxo-7-azabicyclo[3.3.0]octane:

5% Rhodium-on-alumina (700 mg) was added to a solution of(1R,5S)-7-benzyl-2-oxo-7-azabicyclo[3.3.0]oct-3-ene (1.57 g, 7.34 mmol)in ethyl acetate (50 ml), and the mixture was vigorously stirred in ahydrogen atmosphere for 3.5 hours. The insoluble matter was removed byCelite filtration, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to give 1.31 g (6.10 mmol, 83%) of the title compound as acolorless oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 1.75-1.83 (1H, m), 2.08-2.18 (1H, m),2.24-2.32 (1H, m), 2.37-2.49 (2H, m), 2.59-2.64 (1H, m), 2.67 (1H, dd,J=2.5, 9.5 Hz), 2.85-2.93 (1H, m), 3.04 (1H, dd, J=1.5, 9.5 Hz), 3.48(1H, d, J=13.0 Hz), 3.61 (1H, d, J=13.0 Hz), 7.21-7.31 (5H, m).

REFERENCE EXAMPLE 8

(1R,5S)-7-Benzyloxycarbonyl-2-oxo-7-azabicyclo[3.3.0]octane:

A solution of benzyloxycarbonyl chloride (4.28 ml, 30.0 mmol) indichloromethane (15 ml) was added dropwise to a solution of(1R,5S)-7-benzyl-2-oxo-7-azabicyclo[3.3.0]octane (1.31 g, 6.10 mmol) indichloromethane (20 ml) while cooling with ice, and the mixture wasstirred at room temperature for 16 hours. The solvent was removed byevaporation, and the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:1) to give 1.36 g (5.24 mmol,86%) of the title compound as a colorless oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 1.80-1.90 (1H, m), 2.12-2.22 (1H, m),2.35-2.39 (2H, m), 2.76 (1H, dt, J=3.5, 8.5 Hz), 3.01-3.11 (1H, m),3.16-3.26 (1H, m), 3.61-3.66 (1H, m), 3.69-3.78 (1H, m), 5.11-5.12 (2H,m), 7.29-7.38 (5H, m)

REFERENCE EXAMPLE 9

(1′R,5′S)-Spiro[7′-benzyloxycarbonyl-7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane]:

Ethylene glycol (4.46 ml, 80.0 mmol) and p-toluenesulfonic acidmonohydrate (190.2 mg, 1.0 mmol) were added to a solution of(1R,5S)-7-benzyloxycarbonyl-2-oxo-7-azabicyclo[3.3.0]octane (8.27 g,31.9 mmol) in benzene (100 ml), and the mixture was refluxed for 3 hourswhile removing water produced with a Dean-Stark apparatus. After coolingto room temperature, the reaction mixture was poured into a saturatedaqueous solution of sodium hydrogencarbonate and extracted with ethylacetate. The organic layer was washed successively with water and asaturated sodium chloride aqueous solution and dried over anhydroussodium sulfate. The solvent was evaporated to give 9.71 g (quantitative)of the title compound as a crude colorless oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 1.45-1.53 (1H, m), 1.75-1.83 (1H, m),1.89-2.01 (2H, m), 2.61 (1H, dt, J=5.5, 9.0 Hz), 2.74-2.84 (1H, m),3.23-3.33 (1H, m), 3.44-3.62 (3H, m), 3.90-3.92 (4H, m), 5.11-5.14 (2H,m), 7.28-7.37 (5H, m).

REFERENCE EXAMPLE 10

(1′R,5′S)-Spiro[7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane]:

10% Palladium-on-carbon (2.0 g) was added to a solution of the crude(1′R,5′S)-spiro[7′-benzyloxycarbonyl-7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane](9.71 g, 31.9 mmol) in methanol (200 ml), and the mixture was vigorouslystirred in a hydrogen atmosphere for 2 hours. The insoluble matter wasremoved by Celite filtration. Concentration of the residue gave a crudeproduct of the title compound (5.17 g, 30.6mmol, 95%) as a colorlessoily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 1.26-1.34 (1H, m), 1.63-1.69 (1H, m),1.73-1.80 (1H, m), 1.93 (1H, dq, J=7.5, 12.5 Hz), 2.48-2.53 (1H, m),2.62-2.71 (2H, m), 2.76 (1H, dd, J=8.0, 12.0 Hz), 2.92 (1H, dd, J=7.0,11.0 Hz), 3.00 (1H, dd, J=4.0, 12.0 Hz), 3.88-3.95 (4H, m).

REFERENCE EXAMPLE 11

(1′R,5′S)-Spiro[7′-p-anisoyl-7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane]:

p-Anisoyl chloride (6.82 g, 40.0 mmol) was added to a solution of(1′R,5′S)-spiro[7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane] (5.17 g,30.6 mmol) and triethylamine (6.97 ml, 50.0 mmol) in dichloromethane(100 ml) under ice-cooling. The mixture was stirred at room temperaturefor 1 hour, and the reaction mixture was poured into a 10% aqueouscitric acid solution and extracted with ethyl acetate. The organic layerwas washed successively with a saturated aqueous solution of sodiumhydrogencarbonate and a saturated aqueous solution of sodium chlorideand dried over anhydrous sodium sulfate. The solvent was evaporated, andthe residue was purified by silica gel column chromatography(chloroform:methanol=50:1) to give 9.02 g (29.7 mmol, 93%) of the titlecompound as a colorless oily substance.

REFERENCE EXAMPLE 12

(1R,5S)-7-p-Anisoyl-2-oxo-7-azabicyclo[3.3.0]octane:

(1′R,5′S)-Spiro[7′-anisoyl-7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane](9.02 g, 29.7 mmol) was dissolved in 80% acetic acid (150 ml), and thesolution was refluxed for 2.5 hours. After cooling to room temperature,the acetic acid was removed by evaporation. To the residue was added asaturated aqueous solution of sodium hydrogencarbonate, and the mixturewas extracted with ethyl acetate. The organic layer was washed with asaturated sodium chloride aqueous solution and dried over anhydroussodium sulfate. Removal of the solvent by evaporation gave 7.91 g(quantitative) of the title compound as a crude colorless oilysubstance.

REFERENCE EXAMPLE 13

(1R,5S)-2-(N-Benzyl-N-benzyloxycarbonyl)amino-7-p-anisoyl-7-azabicyclo[3.3.0]oct-2-ene:

Benzylamine (3.82 ml, 35.0 mmol) was added dropwise to a mixture of thecrude (1R,5S)-7-p-anisoyl-2-oxo-7-azabicyclo[3.3.0]octane (7.91 g, 29.7mmol), anhydrous magnesium sulfate (10 g), and tetrahydrofuran (100 ml)under cooling with ice, followed by stirring for 1 hour. The insolublematter was removed by filtration, and the filtrate was concentrated. Theresidue was dissolved in benzene (100 ml), and triethylamine (6.27 ml,45.0 mmol) was added thereto. To the mixture was further addedtriphosgene (4.45 g, 15.0 mmol) under ice-cooling, and the mixture wasstirred at room temperature for 1 hour. The insoluble matter was removedby Celite filtration, and the filtrate was concentrated. The residue wasdissolved in tetrahydrofuran (30 ml), and the resulting solution wasadded dropwise to a solution of benzyloxysodium. (36.0 mmol) intetrahydrofuran (50 ml) under cooling with ice. After stirring themixture at room temperature for 30 minutes, a saturated aqueous solutionof ammonium chloride was added thereto while cooling with ice, and themixture was extracted with ethyl acetate. The extract was washedsuccessively with water and a saturated aqueous solution of sodiumchloride, and dried over anhydrous sodium sulfate. The solvent wasremoved by evaporation, and the residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=1:1) to give the titlecompound (3.39 g, 7.02 mmol, 24%) as a colorless oily substance.

REFERENCE EXAMPLE 14

(1R,2R,6S)-1-(N-Benzyl-N-benzyloxycarbonyl)amino-4-p-anisoyl-4-azatricyclo[6.1.0.0^(2,6)]nonane:

A 1M n-hexane solution (20.0 ml) of diethylzinc (20.0 mmol) was addeddropwise to a solution of(1R,5S)-2-(N-benzyl-N-benzyloxycarbonyl)amino-7-anisoyl-7-azabicyclo[3.3.0]oct-2-ene(3.39 g, 7.02 mmol) and diiodomethane (3.06 ml, 38.0 mmol) indichloromethane (50 ml) at room temperature, followed by stirring for 16hours. To the reaction mixture was added a saturated aqueous solution ofammonium chloride, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with a sodium thiosulfate aqueous solution anda saturated sodium chloride aqueous solution, and dried over anhydroussodium sulfate. The solvent was evaporated, and the residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give2.64 g (5.32 mmol, 76%) of the title compound as a colorless oilysubstance.

REFERENCE EXAMPLE 15

(1R,2R,6S)-1-t-Butoxycarbonylamino-4-p-anisoyl-4-azatricyclo[6.1.0.0^(2,6)]nonane:

To a methanol (100 ml) solution of(1R,2R,6S)-1-(N-benzyl-N-benzyloxycarbonyl)amino-4-p-anisoyl-4-azatricyclo[6.1.0.0^(2,6)]nonane(2.64 g, 5.32 mmol) was added 10% palladium-on-carbon (2.0 g), and themixture was stirred vigorously in a hydrogen atmosphere for 15 hours.The insoluble matter was removed by Celite filtration, and the filtratewas concentrated. The residue and triethylamine (1.39 ml, 10.0 mmol)were dissolved in dichloromethane (50 ml), and di-t-butyl dicarbonate(2.18 g, 10 mmol) was added to the solution at room temperature,followed by stirring for 2 hours. After concentration, the residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:2) to give 970 mg (2.60 mmol, 49%) of the title compound as acolorless oily substance.

REFERENCE EXAMPLE 16

(1R,2R,6S)-1-t-Butoxycarbonylamino-4-p-methoxybenzyl-4-azatricyclo[6.1.0.0^(2,6)]nonane:

A 1M tetrahydrofuran solution (7.0 ml) of a boranetetrahydrofurancomplex (7.0 mmol) was added dropwise to a tetrahydrofuran (20 ml)solution of(1R,2R,6S)-1-t-butoxycarbonylamino-4-p-anisoyl-4-azatricyclo[6.1.0.0^(2,6)]nonane(970 ml, 2.60 mmol) while cooling with ice, and the mixture was stirredat room temperature for 1 hour. While cooling with ice, water was addedto the reaction mixture to decompose the excess borane-tetrahydrofurancomplex. A 1N sodium hydroxide aqueous solution (10 ml) was addedthereto, followed by refluxing for 6 hours. After cooling to roomtemperature, the reaction mixture was extracted with diethyl ether. Theextract was dried over anhydrous sodium sulfate, the solvent wasevaporated, and the residue was purified by silica gel columnchromatography (chloroform:methanol=20:1) to give 453 mg (1.26 mmol,48%) of the title compound as a colorless oily substance.

REFERENCE EXAMPLE 17

(1R,2R,6S)-1-t-butoxycarbonylamino-4-azatricyclo[6.1.0.0^(2,6)]nonane:

To a methanol (20 ml) solution of the(1R,2R,6S)-1-t-butoxycarbonylamino-4-p-methoxybenzyl-4-azatricyclo[6.1.0.0^(2,6)]-nonane(453 mg, 1.26 mmol) was added 10% palladium-on-carbon (400 mg), and themixture was stirred vigorously in a pressurized (5 kg/cm²) hydrogenatmosphere for 30 hours. The insoluble matter was removed by Celitefiltration, and the filtrate was concentrated to give 286 mg (1.20 mmol,95%) of the title compound as a colorless oily substance.

REFERENCE EXAMPLE 18

(1R,5S)-2-(N-Benzyl-N-benzyloxycarbonyl)amino-7-benzyloxycarbonyl-7-azabicyclo[3.3.0]oct-2-ene:

Benzylamine (546 μl, 5.0 mmol) was added dropwise to a mixture of(1R,5S)-7-benzyloxycarbonyl-2-oxo-7-azabicyclo[3.3.0]octane (1.0 g, 3.86mmol), anhydrous magnesium sulfate (1.5 g), and tetrahydrofuran (15 ml)under cooling with ice, followed by stirring for 1 hour. The insolublematter was removed by filtration, and the filtrate was concentrated. Theresidue was dissolved in benzene (15 ml), and triethylamine (753 μl,35.0 mmol) was added thereto. To the mixture was further addedtriphosgene (534 mg, 1.8 mmol) under ice-cooling, and the mixture wasstirred at room temperature for 1 hour. The insoluble matter was removedby Celite filtration, and the filtrate was concentrated. The residue wasdissolved in tetrahydrbfuran (10 ml), and the resulting solution wasadded dropwise to a solution of benzyloxysodium (6.0 mmol) intetrahydrofuran (5 ml) under cooling with ice. After stirring themixture at room temperature for 30 minutes, a saturated aqueous solutionof ammonium chloride was added thereto while cooling with ice, and themixture was extracted with ethyl acetate. The extract was washedsuccessively with water and a saturated aqueous solution of sodiumchloride, and dried over anhydrous sodium sulfate. The solvent wasremoved by evaporation, and the residue was dissolved in dichloromethane(15 ml). Triethylamine (1.25 ml, 9.0 mmol) and 4-dimethylaminopyridine(50 mg) were added to the solution, and acetic anhydride (660 μl, 7.0mmol) was added thereto dropwise at room temperature. After stirring atroom temperature for 30 minutes, the reaction mixture was poured into a10% aqueous solution of citric acid, followed by extraction with ethylacetate. The organic layer was washed successively with a saturatedsodium hydrogencarbonate aqueous solution and then a saturated sodiumchloride aqueous solution, and dried over anhydrous sodium sulfate. Thesolvent was evaporated, and the residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=1:1) to give 1.07 g (2.22mmol, 58%) of the title compound as a colorless oily substance.

REFERENCE EXAMPLE 19

(1R,2R,6S)-1-(N-Benzyl-N-benzyloxycarbonyl)amino-4-benzyloxycarbonyl-4-azatricyclo[6.1.0.0^(2,6)]nonane:

A1M n-hexane solution (10.0 ml) of diethylzinc (10.0 mmol) was addeddropwise to a solution of(1R,5S)-2-(N-benzyl-N-benzyloxycarbonyl)amino-7-benzyloxycarbonyl-7-azabicyclo[3.3.0]oct-2-ene(1.07 g, 2.22 mmol) and diiodomethane (1.57 ml, 19.5 mmol) indichloromethane (15 ml) at room temperature, followed by stirring for 16hours. To the reaction mixture was added a saturated aqueous solution ofammonium chloride, and the mixture was extracted with ethyl acetate. Theorganic layer was washed successively with a sodium thiosulfate aqueoussolution and a saturated sodium chloride aqueous solution, and driedover anhydrous sodium sulfate. The solvent was evaporated, and theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=3:1) to give 785 mg (1.58 mmol, 71%) of the title compound as acolorless oily substance.

REFERENCE EXAMPLE 20

(1R,2R,6S)-1-Amino-4-azatricyclo[6.1.0.0^(2,6)]nonane:

To a methanol (30 ml) solution of the (1R,2R,6S)-1-(N-benzyl-N-benzyloxycarbonyl)amino-4-benzyloxycarbonyl-4-azatricyclo[6.1.0.0^(2,6)]nonane(785 mg, 1.58 mmol) was added 10% palladium-on-carbon (800 mg), and themixture was vigorously stirred in a hydrogen atmosphere for 9 hours. Theinsoluble matter was removed by Celite filtration, and the filtrate wasconcentrated to give 283 mg of the title compound as a colorless oilysubstance. [α]_(D)=−21.15 (c=0.26, methanol, T=24.5° C.)

REFERENCE EXAMPLE 21

Spiro[7′-benzyloxycarbonyl-7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane]:

Ethylene glycol (44.6 ml, 800 mmol) and p-toluenesulfonic acidmonohydrate (951 mg, 5 mmol) were added to a solution of7-benzyloxycarbonyl-2-oxo-7-azabicyclo[3.3.0]octane (90.69 g, 350 mmol)in benzene (800 ml), and the mixture was refluxed for 3 hours whileremoving water produced with a Dean-Stark apparatus. After cooling toroom temperature, the reaction mixture was poured into a saturatedaqueous solution of sodium hydrogencarbonate and extracted with ethylacetate. The organic layer was washed successively with water and asaturated sodium chloride aqueous solution and dried over anhydroussodium sulfate. The solvent was evaporated to give 104.15 g (343 mmol,98%) of the title compound as a crude colorless oily substance. ¹H-NMR(400 MHz, CDCl₃) δ: 1.45-1.53 (1H, m), 1.75-1.83 (1H, m), 1.89-2.01 (2H,m), 2.61 (1H, dt, J=5.5, 9.0 Hz), 2.74-2.84 (1H, m), 3.23-3.33 (1H, m),3.44-3.62 (3H, m), 3.90-3.92 (4H, m), 5.11-5.14 (2H, m), 7.28-7.37 (5H,m).

REFERENCE EXAMPLE 22

Spiro[7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane]:

To a methanol (1000 ml) solution of the crudespiro[7′-benzyloxycarbonyl-7′-azabicyclo[3.3.0]6octane-1,2′-2,5-dioxolane](104.15 g, 343 mmol) was added 10% palladium-on-carbon (15 g), and themixture was vigorously stirred in a hydrogen atmosphere for 2 hours. Theinsoluble matter was removed by Celite filtration, and the filtrate wasconcentrated to give the title compound as a crude colorless oilysubstance in a quantitative yield.

¹H-NMR (400 MHz, CDCl₃) δ: 1.26-1.34 (1H, m), 1.63-1.69 (1H, m),1.73-1.80 (1H, m), 1.93 (1H, dq, J=7.5, 12.5 Hz), 2.48-2.53 (1H, m),2.62-2.71 (2H, m), 2.76 (1H, dd, J=8.0, 12.0 Hz), 2.92 (1H, dd, J=7.0,11.0 Hz), 3.00 (1H, dd, J=4.0, 12.0 Hz), 3.88-3.95 (4H, m)

REFERENCE EXAMPLE 23

Spiro[7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane] L(+)-Tartrate (F1):

A methanol (200 ml) solution ofspiro[7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane] (39.46 g, 233 mmol)was added to a methanol (550 ml) solution of L(+)-tartaric acid (34.97g, 233 mmol). The mixture was heated under reflux for 2 hours, followedby filtration to collect the precipitated crystals (37.70 g). Thecrystals were suspended in methanol (380 ml), followed by heating underreflux for 2 hours. The precipitated crystals (29.73 g) were collectedby filtration, again suspended in methanol (300 ml), and heat-refluxedfor 6 hours, followed by filtration to collect precipitated crystals(26.49 g)

¹H-NMR (400 MHz, D₂O) δ: 1.43-1.51 (1H, m), 1.73-1.81 (1H, m), 1.89-2.05(2H, m), 2.84-2.91 (1H, m), 2.95-3.07 (2H, m), 3.26-3.35 (2H, m), 3.42(1H, dd, J=8.0, 11.5 Hz), 3.97 (4H, s), 4.47 (2H, s).

REFERENCE EXAMPLE 24

Spiro[7′-p-anisoyl-7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane] (F1):

The spiro[7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane] L(+)-tartrate(48.7 g, 153 mmol) was added to a mixture of a 2N sodium hydroxideaqueous solution (300 ml) and tetrahydrofuran (400 ml) under coolingwith ice. A tetrahydrofuran (100 ml) solution of p-anisoyl chloride(34.12 g, 200 mmol) was added thereto dropwise, followed by stirring atroom temperature for 1 hour. The organic layer was separated, washedsuccessively with a 10% citric acid aqueous solution and a saturatedsodium chloride aqueous solution, and dried over anhydrous sodiumsulfate. The solvent was evaporated, and the residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=1:1) to give45.23 g (149 mmol, 97%) of the title compound as a colorless oilysubstance. The TLC and ¹H-NMR data of the product were in agreement withthose of Reference Example 11. HPLC analysis under the followingconditions proved that the optical purity of the product was 98.4% ee.

HPLC Conditions:

Column: DAICEL CHIRALCEL AD; 0.46×25 cm

Mobile Layer: hexane:ethanol=1:2

Flow Rate: 0.5 ml/min

Detection: UV (254 nm)

REFERENCE EXAMPLE 25

Spiro[7′-p-anisoyl-7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane]:

p-Anisoyl chloride (17.1 g, 100 mmol) was added to a solution ofspiro[7′-azabicyclo[3.3.0]octane-1,2-2,5-dioxolane](15.5 g, 91.8 mmol)and triethylamine (20.9 ml, 150 mmol) in dichloromethane (300 ml) underice-cooling. The mixture was stirred at room temperature for 30 minutes,and the reaction mixture was poured into a 10% aqueous citric acidsolution and extracted with ethyl acetate. The organic layer was washedsuccessively with a saturated aqueous solution of sodiumhydrogencarbonate and a saturated aqueous solution of sodium chlorideand dried over anhydrous sodium sulfate. The solvent was evaporated, andthe residue was purified by silica gel column chromatography(chloroform:methanol=50:1) to give 27.6 g (90.9 mmol, 99%) of the titlecompound as a colorless oily substance.

REFERENCE EXAMPLE 26

(+)-7-p-Anisoyl-2-oxo-7-azabicyclo[3.3.0]octane (F1):

Spiro[7′-anisoyl-7′-azabicyclo[3.3.0]octane-1,2′-2,5-dioxolane] (27.6 g,90.9 mmol) was dissolved in 80% acetic acid (450 ml), and the solutionwas heat-refluxed for 2.5 hours. After cooling the reaction mixture toroom temperature, the acetic acid was evaporated. To the residue wasadded a saturated aqueous solution of sodium hydrogencarbonate, and themixture was extracted with ethyl acetate. The organic layer was washedwith a saturated sodium chloride aqueous solution and dried overanhydrous sodium sulfate. The solvent was removed by evaporation, andthe residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=1:1) to give 24.1 g (quantitative) of a racemateof the title compound as a colorless oily substance. The TLC and ¹H-NMRdata of the product were in agreement with those of the product ofReference Example 12 (optically active compound). The resulting productwas separated into the optically active compounds by HPLC under thefollowing conditions to give 10.1 g (42%) of a high-polar opticallyactive compound (Fl) and 9.69 g (40%) of a low-polar optically activecompound (F2).

HPLC Conditions:

Column: DAICEL CHIRALCEL AD; 2×25 cm

Mobile Layer: hexane:ethanol:methanol=1:1:1

Flow Rate: 5 ml/min

Detection: UV (254 nm)

F1:

[α]_(D)=77.1 (c=0.18, methanol, T=23.7° C.)

F2:

[α]_(D)=−69.2 (c=0.29, methanol, T=23.7° C.)

Each of the resulting optically active compounds (F1 and F2) was led to1-t-butoxycarbonylamino-4-azatricyclo[6.1.0.0^(2,6)]nonane (F1 and F2)in accordance with Reference Examples 13, 14, 15, 16, and 17.

EXAMPLE 2

10-{(1R,2R,6S)-1-Amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4]benzoxazine-6-carboxylicAcid:

9,10-Difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4]benzoxazine-6-carboxylicacidBF₂ chelate (329 mg, 1.0 mmol) was added to a solution of(1R,2R,6S)-1-t-butoxycarbonylamino-4-azatricyclo[6.1.0.0^(2,6)]nonane(F1; 286 mg, 1.20 mmol) and triethylamine (348 μl, 2.5 mmol) in dimethylsulfoxide (3 ml) at room temperature, followed by stirring at roomtemperature for 15 hours. Triethylamine was evaporated from the mixture,and water was added to the residue. The crystals thus precipitated werecollected by filtration. To the crystals were added 90% methanol (30 ml)and triethylamine (5 ml), and the mixture was heated under reflux for 5hours. Methanol was evaporated, and a 10% citric acid aqueous solutionwas added to the residue, and the mixture was extracted with chloroform.The organic layer was washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. The solvent wasremoved by evaporation, and the residue was dissolved in dichloromethane(5 ml). Trifluoroacetic acid (10 ml) was added to the solution whilecooling with ice, and the mixture was stirred at room temperature for 1hour, followed by concentration. To the residue was added a hydrochloricacid aqueous solution. The mixture was washed with chloroform, adjustedto pH 7.8 with a sodium hydroxide aqueous solution, and extracted withchloroform. The extract was dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was recrystallized from 2-propanolto give 124 mg (0.31 mmol, 31%) of the title compound as yellowcrystals.

¹H-NMR (400 MHz, 0.1N-NaOD) δ: 0.46-0.54 (1H, m), 0.55 (1H, dd, J=5.0,8.5 Hz), 1.23 (1H, dt, J=4.0, 8.5 Hz), 1.41 (3H, d, J=7.0 Hz), 1.71-1.83(2H, m), 2.22-2.32 (1H, m), 2.66 (1H, q, J=8.5 Hz), 3.13-3.17 (1H, m),3.46 (1H, t, J=9.0 Hz), 3.70-3.81 (2H, m), 4.19-4.25 (1H, m), 4.38-4.41(1H, m), 4.47-4.54 (1H, m), 7.43 (1H, d, J=13.5 Hz), 8.22 (1H, s);

[α]_(D)=−93.00 (c=0.30, 1N NaOH aqueous solution, T=24.0° C.)

Melting point: 216-221° C. (decomposition)

Elemental Analysis for C₂₁H₂₂FN₃O₄:

Calcd.: C, 63.15; H, 5.55; N, 10.52

Found: C, 62.90; H, 5.63; N, 10.22

EXAMPLE 3

10-{(1R,2R,6S)-1-Amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4]benzoxazine-6-carboxylicAcid:

9,10-Difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4]benzoxazine-6-carboxylicacidBF₂ chelate (74 mg, 0.225 mmol) was added to a solution of(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonane (73.6 mg, 0.533mmol) and triethylamine (74.3 μl, 0.533 mmol) in dimethyl sulfoxide (3ml) at room temperature, followed by stirring at room temperature for 5hours. The solvent was evaporated, and to the residue were added 90%ethanol (40 ml) and triethylamine (1 ml). The mixture was heated underreflux for 3 hours. The ethanol was evaporated, and a hydrochloric acidaqueous solution was added to the residue. The mixture was washed withchloroform, adjusted to pH 7.4 with a sodium hydroxide aqueous solution,and extracted with chloroform. The extract was dried over anhydroussodium sulfate. The solvent was removed by evaporation, and the residuewas recrystallized from ethanol to give 69 mg (0.173 mmol, 77%) of thetitle compound as yellow crystals. The ¹H-NMR and specific rotation dataof the product were in agreement with those of Example 1.

Elemental Analysis for C₂₁H₂₂FN₃O₄:

Calcd.: C, 63.15; H, 5.55; N, 10.52

Found: C, 62.98; H, 5.77; N, 10.43

EXAMPLE 4

10-{1-Amino-4-azatricyclo [6.1.0.0^(2,6)]nonan-4-yl}-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4]benzoxazine-6-carboxylicAcid (F2):

9,10-Difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4]benzoxazine-6-carboxylic acidBF₂ chelate (526 mg, 1.6mmol) was added to a solution of(1S,2S,6R)-1-t-butoxycarbonylamino-4-azatricyclo [6.1.0.0^(2,6)]nonane(F2; 395 mg, 1.66 mmol) and triethylamine (557 μl, 4.0 mmol) in dimethylsulfoxide (3 ml) at room temperature, followed by stirring at roomtemperature for 15 hours. Triethylamine was evaporated from the mixture,and water was added to the residue. The crystals thus precipitated werecollected by filtration. To the crystals were added 90% methanol (30 ml)and triethylamine (5 ml), and the mixture was heated under reflux for 5hours. Methanol was evaporated, and a 10% citric acid aqueous solutionwas added to the residue, and the mixture was extracted with chloroform.The organic layer was washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. The solvent wasremoved by evaporation, and the residue was dissolved in dichloromethane(5 ml). Trifluoroacetic acid (10 ml) was added to the solution whilecooling with ice, and the mixture was stirred at room temperature for 1hour, followed by concentration. To the residue was added a hydrochloricacid aqueous solution, washed with chloroform, adjusted to pH 7.8 with asodium hydroxide aqueous solution, and extracted with chloroform. Theextract was dried over anhydrous sodium sulfate, and the solvent wasevaporated. The residue was recrystallized from 2-propanol to give 180mg (0.45 mmol, 28%) of the title compound as yellow crystals.

¹H-NMR (400MHz, 0.1N-NaOD) δ: 0.46-0.54 (1H, m), 0.55 (1H, dd, J=5.0,8.5 Hz), 1.23 (1H, dt, J=4.0, 8.5 Hz), 1.39 (3H, d, J=7.0 Hz), 1.71-1.83(2H, m), 2.22-2.32 (1H, m), 2.66 (1H, q, J=8.5 Hz), 3.13-3.17 (1H, m),3.46 (1H, t, J=9.0 Hz), 3.70-3.81 (2H, m), 4.19-4.25 (1H, m), 4.38-4.41(1H, m), 4.47-4.54 (1H, m), 7.41 (1H, d, J=14.0 Hz), 8.20 (1H, s);

[α]_(D)=−6.41 (c=0.39, 1N NaOH aqueous solution, T=24.2° C.)

Melting point: 176-180 (decomposition)

Elemental analysis for C₂₁H₂₂FN₃O₄:

Calcd.: C, 63.15; H, 5.55; N, 10.52

Found: C, 63.01; H, 5.65; N, 10.29

EXAMPLE 5

7-{1-Amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicAcid (F1):

6,7-Difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacidBF₂ chelate (433 mg, 1.2 mmol) was added to a solution of1-t-butoxycarbonylamino-4-azatricyclo[6.1.0.0^(2,6)]nonane (F1; 300 mg,1.26 mmol) and triethylamine (697 μl, 5.0 mmol) in dimethyl sulfoxide (3ml) at room temperature, followed by stirring at room temperature for 15hours. Triethylamine was evaporated from the mixture, and water wasadded to the residue. The crystals thus precipitated were collected byfiltration. To the crystals were added 90%methanol (30 ml) andtriethylamine (5 ml), and the mixture was heated under reflux for 5hours. Methanol was evaporated, and a 10% citric acid aqueous solutionwas added to the residue, and the mixture was extracted with chloroform.The organic layer was washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous sodium sulfate. The solvent wasremoved by evaporation, and the residue was dissolved in dichloromethane(5 ml). Trifluoroacetic acid (10 ml) was added to the solution whilecooling with ice, and the mixture was stirred at room temperature for 1hour, followed by concentration. To the residue was added a hydrochloricacid aqueous solution, washed with chloroform, adjusted to pH 7.8 with asodium hydroxide aqueous solution, and extracted with chloroform. Theextract was dried over anhydrous sodium sulfate, and the solvent wasevaporated. The residue was recrystallized from 2-propanol to give 180mg (0.41 mmol, 34%) of the title compound as yellow crystals.

¹H-NMR (400 MHz, 0.1N-NaOD) δ: 0.56-0.60 (2H, m), 1.25-1.35 (3H, m),1.41-1.52 (1H, m), 1.72 (1H, ddd, J=4.0, 9.0, 13.0 Hz), 1.81 (1H, dd,J=8.5, 12.5 Hz), 2.26-2.34 (1H, m), 2.70 (1H, q, J=8.0 Hz), 3.23 (1H, d,J=10.5 Hz), 3.45 (1H, t, J=9.5 Hz), 3.53 (3H, s), 3.79-3.84 (2H, m),3.95 (1H, dt, J=5.5, 9.0 Hz), 4.96 (1H, ddd, J=5.5, 8.5, 63.5 Hz), 7.59(1H, d, J=14.5 Hz), 8.32 (1H, d, J=3.5 Hz);

[α]_(D)=−69.39 (c=0.49, NaOH aqueous solution, T=24.4° C.)

Melting point: 146-159° C. (decomposition)

Elemental analysis for C₂₂H₂₃F₂N₃O₄0.5H₂O:

Calcd.: C, 59.99; H, 5.49; N, 9.54

Found: C, 59.79; H, 5.27; N, 9.49

EXAMPLE 6

5-Amino-7-{1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-4-carboxylicAcid (F1):

1-t-Butoxycarbonylamino-4-azatricyclo[6.1.0.0^(2,6)]nonane (F1; 498 mg,2.09 mmol) and triethylamine (5 ml) were added to dimethyl sulfoxide (10ml) at room temperature, and5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (625 mg, 2.0 mmol) was added thereto, followed by stirring at anexternal temperature of 120° C. for 15 hours. Triethylamine and dimethylsulfoxide were removed by evaporation, and a 10% citric acid aqueoussolution was added to the residue. The mixture was extracted withchloroform, and the extract was dried over anhydrous sodium sulfate. Thesolvent was evaporated, and concentrated hydrochloric acid was added tothe residue. The mixture was washed with chloroform, adjusted to pH 7.8with a sodium hydroxide aqueous solution, and extracted with chloroform.The extract was dried over anhydrous sodium sulfate, and the solvent wasevaporated. The residue was recrystallized from 2-propanol to give 74 mg(0.17 mmol, 9%) of the title compound as yellow crystals.

¹H-NMR (400 MHz, 0.1N-NaOD) δ: 0.47 (1H, d, J=4.5 Hz), 0.56 (1H, dd,J=4.5, 8.0 Hz), 0.92-1.03 (1H, m), 1.24-1.26 (1H, m), 1.36-1.46 (1H, m),1.62-1.67 (1H, m), 1.74 (1H, dd, J=8.0, 12.0 Hz), 2.17-2.26 (1H, m),2.61 (1H, q, J=7.5 Hz), 2.87 (1H, d, J=9.5 Hz), 3.11 (1H, t, J=9.0 Hz),3.69-4.03 (3H, m), 4.60-4.99 (1H, m), 8.20 (1H, d, J=3.5 Hz)

Elemental analysis for C₂₂H₂₄F₂N₄O₃:

Calcd.: C, 61.39; H, 5.62; N, 13.02

Found: C, 61.59; H, 5.64; N, 12.77

REFERENCE EXAMPLE 27

(1R,5S)-2-(N-Benzyl-N-benzyloxycarbonyl)amino-7-p-anisoyl-7-azabicyclo[3.3.0]-oct-2-ene(alternative to the method of Reference Example 13):

A solution of benzylamine (10.9 ml, 100 mmol) in tetrahydrofuran (50 ml)was added dropwise to a mixture of(1R,5S)-7-p-anisoyl-2-oxo-7-azabicyclo[3.3.0]octane (20.72 g, 79.9mmol), anhydrous magnesium sulfate (20 g), and tetrahydrofuran (200 ml)while cooling with ice. After stirring the mixture for 1 hour, theinsoluble matter was removed by filtration, and the filtrate wasconcentrated. The residue thus obtained was dissolved in dichloromethane(100 ml), and N,N-dimethylaniline (15.2 ml, 120 mmol) was added to thesolution. Benzylchloroformate (17.13 ml, 120 mmol) was added dropwise tothe mixture under ice-cooling, followed by stirring at room temperaturefor 2 hours. The reaction mixture was added to a 1N hydrochloric acidaqueous solution and extracted with ethyl acetate. The extract waswashed successively with a saturated sodium hydrogencarbonate aqueoussolution and a saturated sodium chloride aqueous solution and dried overanhydrous sodium sulfate. The solvent was removed by evaporation, andthe residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=1:1) to give 31.64 g (65.5 mmol, 82%) of thetitle compound as a colorless oily substance.

REFERENCE EXAMPLE 28

(1R,2R,6S)-1-t-Butoxycarbonylamino-4-p-methoxybenzyl-4-azatricyclo[6.1.0.0^(2,6)]nonane(alternative to the method of Reference Example 16):

Lithium aluminum hydride (1.37 g, 36 mmol) was added to atetrahydrofuran (200 ml) solution of(1R,2R,6S)-1-t-butoxycarbonylamino-4-p-anisoyl-4-azatricyclo[6.1.0.0^(2,6)]nonane(13.40 g, 35.98 mmol) while cooling with ice, and the mixture wasstirred at room temperature for 1 hour. To the reaction mixture wereadded dropwise water (1.37 ml), a 15% sodium hydroxide aqueous solution(1.37 ml), and water (4.11 ml) in this order while cooling with ice,followed by stirring at room temperature for 18 hours. The insolublematter was removed by Celite filtration, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (chloroform:methanol=20:1) to give 8.24 g (23.00 mmol,64%) of the title compound as a colorless oily substance.

REFERENCE EXAMPLE 29

(1R,5S)-2-(N-Benzyl-N-benzyloxycarbonyl)amino-7-benzyloxycarbonyl-7-azabicyclo[3.3.0]oct-2-ene:

Lithium aluminum hydride (1.37 g, 36 mmol) was added to atetrahydrofuran (200 ml) solution of(1R,5S)-1-t-butoxycarbonylamino-4-p-anisoyl-4-azatricyclo[6.1.0.0^(2,6)]nonane(13.40 g, 35.98 mmol) while cooling with ice, and the mixture wasstirred at room temperature for 1 hour. To the reaction mixture wereadded dropwise water (1.37 ml), a 15% sodium hydroxide aqueous solution(1.37 ml), and water (4.11 ml) in this order while cooling with ice,followed by stirring at room temperature for 18 hours. The insolublematter was removed by Celite filtration, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (chloroform:methanol=20:1) to give 8.24 g (23.00 mmol,64%) of the title compound as a colorless oily substance.

REFERENCE EXAMPLE 30

11-Aza-11-benzyl-tetracyclo[7.3.1^(4,7)0^(3,8)0]tridec-5-en-2-one:

Benzylbutoxymethyltrimethylsilylamine (4.59 g, 16.4 mmol) was added to adichloroethane (15 ml) solution oftricyclo[5.2.1.0^(2,6)]deca-4,8-dien-3-one (Synthesis, p. 687 (1994))(2.00 g, 13.7 mmol), and trifluoroacetic acid (15 μl) was further addedthereto at room temperature. The mixture was stirred at that temperaturefor 2 hours and then at 50° C. for 16 hours. A 10% citric acid aqueoussolution was added to the reaction mixture. The organic layer wasseparated, and to the aqueous layer was added a saturated sodiumhydrogencarbonate aqueous solution, followed by extraction withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate. The solvent was removed by evaporation to give 3.40 g (89%) ofthe title compound as a crude product. The product was used in thesubsequent reaction without purification. ¹H-NMR (CDCl₃) δ: 1.38 (1H, d,J=8.3 Hz), 2.18-2.22 (1H, m), 2.32-2.37 (3H, m), 2.44-2.48 (1H, m),2.63-2.68 (2H, m), 2.88 (1H, d, J=7.8 Hz), 3.00-3.06 (2H, m), 3.20-3.22(1H, m), 3.47 (2H, AB-q, J=13.2 Hz), 6.06-6.08 (1H, m), 6.15-6.17 (1H,m), 7.22-7.31 (5H, m)

REFERENCE EXAMPLE 31

7-Benzyl-2-oxo-7-azabicyclo[3.3.0]oct-3-ene:

A solution of11-aza-11-benzyl-tetracyclo[7.3.1^(4,7)0^(3,8)0]tridec-5-en-2-one (3.40g, 12.17 mmol) in diphenyl ether (70 ml) was stirred at 220° C. for 20minutes. To the reaction mixture was further added diphenyl ether (130ml), followed by stirring at 220° C. for an additional 20 minute period.After cooling to room temperature, diethyl ether was added thereto, andthe reaction mixture was extracted with a 10% citric acid aqueoussolution. The combined aqueous layer was washed with dichloromethane.Sodium hydrogencarbonate was added thereto, and a saturated sodiumhydrogencarbonate aqueous solution was added to make the mixturealkaline. The mixture was extracted with dichloromethane. The organiclayer was dried over anhydrous sodium sulfate. The solvent wasevaporated, and the residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:1) to give 1.45 g (56%) of thetitle compound.

¹H-NMR (CDCl₃) δ: 2.31 (1H, t, J=8.8 Hz), 2.36 (1H, t, J=8.8 Hz),2.71-2.75 (1H, m), 2.79 (1H, d, J=9.3 Hz), 3.10 (1H, d, J=9.3 Hz),3.36-3.41 (1H, m), 3.55 (2H, AB-q, J=13.2 Hz), 6.24 (1H, d, J=5.4 Hz),7.20-7.35 (5H, m), 7.55 (1H, dd, J=3.0, 5.8 Hz)

REFERENCE EXAMPLE 32

7-Benzyl-2-oxo-7-azabicyclo[3.3.0]octane:

To an ethyl acetate (50 ml) solution of7-benzyl-2-oxo-7-azabicyclo[3.3.0]oct-3-ene (1.45 g, 6.78 mmol) wasadded 5% rhodium-on-alumina (700 mg), and the mixture was stirredvigorously in a hydrogen atmosphere for 3.5 hours. The insoluble matterwas removed by Celite filtration, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to give 1.22 g (5.70 mmol, 84%) of the title compound as acolorless oily substance. The TLC and ¹H-NMR data of the product were inagreement with those of the product of Reference Example 1.

EXAMPLE 7

7-(1-Amino-4-azabicyclo[6.1.0.0^(2,6)]nonan-4-yl)-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicAcid:

(1R,2R,6S)-1-t-Butoxycarbonylamino-4-azatricyclo-[6.1.0.0^(2,6)]nonane(1.20 mmol) was dissolved in dimethyl sulfoxide (1.2 ml), and6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacidBF₂ chelate (345 mg, 1.00 mmol) and triethylamine (0.167 ml) wereadded to the solution. The mixture was stirred in a nitrogen atmospherefor 132 hours. The solvent was removed by evaporation, and water wasadded to the residue. Yellow crystals thus precipitated were collectedby filtration and washed with water. To the crystals wereadded90%methanol (50 ml) and triethylamine (2 ml), and the mixture washeated under reflux for 3 hours. Methanol was evaporated, andconcentrated hydrochloric acid (10 ml) was added dropwise to the residuewhile cooling with ice, followed by stirring at room temperature for 1hour. Water (20 ml) was added to the reaction mixture, and the mixturewas washed with chloroform (30 ml×3), adjusted to pH 12.0 with a sodiumhydroxide aqueous solution, then adjusted to pH 7.4 with 1N hydrochloricacid, and extracted with chloroform (150 ml×3). The combined organiclayer was dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure. The residue waspurified by preparative TLC. The resulting crude product wasrecrystallized from ethanol and dried under reduced pressure to give 51mg (12%) of the title compound as yellow powder.

¹H-NMR (400 MHz, 0.1NaOD) δ: 0.59-0.67 (2H, m), 1.37-1.40 (1H, m),1.57-1.65 (1H, m), 1.80-1.89 (2H, m), 2.37-2.41 (1H, m), 2.53 (3H, s),2.77-2.85 (1H, m), 3.04-3.09 (1H, m), 3.27-3.36 (1H, m), 3.83-3.93 (1H,m), 4.05-4.11 (1H, m), 5.04 (1H, brd, J=58.19 Hz), 7.71 (1H, d, J=14.16Hz), 8.44 (1H, d, J=3.4lHz)

Elemental analysis for C₂₂H₂₃F₂N₃O₃0.5H₂O:

Calcd.: C, 62.25; H, 5.70; N, 9.90

Found: C, 62.05; H, 5.54; N, 9.61

The antimicrobial activity of the compounds according to the presentinvention was determined in accordance with the standard methodspecified by the Japan Chemotherapeutic Society. The results obtained,being expressed in terms of minimum inhibitory concentration (MIC;μg/ml), are shown in the following Table.

Compound of Example Microorganism 1 2 5 6 7 E. coli, NIHJ ≦0.003 ≦0.003≦0.003 ≦0.003 ≦0.003 S. flexneli, 2A 5503 ≦0.003 0.006 ≦0.003 ≦0.003≦0.003 Pr. vulgaris, 08601 0.10 0.025 0.006 0.025 ≦0.003 Pr. Mirabilis,IFO-3849 0.05 0.10 ≦0.003 0.025 0.013 Ser. Marcescens, 10100 0.10 0.050.05 0.05 0.025 Ps. Aeruginosa, 32104 0.20 0.20 0.10 0.10 0.05 Ps.Aeruginosa, 32121 0.20 0.05 0.05 0.025 0.025 Ps. Maltophilia, 0.05 0.200.05 0.025 0.025 11D-1275 S. aureaus, 209P ≦0.003 0.006 ≦0.003 ≦0.003≦0.003 S. epidermidis, 56500 0.006 0.025 ≦0.003 ≦0.003 ≦0.003 Str.Pyogenes, G-36 0.006 0.013 ≦0.003 ≦0.003 ≦0.003 Str. Faecalis, 0.0250.05 0.025 0.013 0.013 ATCC-19433 S. aureus, 870307 0.10 0.20 0.013 0.050.013 S. pneumoniae, J24 ≦0.003 0.013 ≦0.003 ≦0.003 ≦0.003

Industrial Applicability:

The compound according to the present invention possesses excellentantimicrobial activity over a broad range of both Gram negative and Grampositive bacteria and, in particular, exhibits potent antimicrobialactivity even on quinolone-resistant bacteria, while showingsatisfactory pharmacokinatics and safety, and are useful as anantimicrobial compound.

What is claimed is:
 1. A compound represented by formula (I):

wherein R¹ and R² each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms which may be substituted with oneor more substituents selected from the group consisting of a hydroxylgroup, a halogen atom, an alkylthio group having 1 to 6 carbon atoms,and an alkoxyl group having 1 to 6 carbon atoms; R³ represents ahydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, analkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6carbon atoms or an alkylthio group having 1 to 6 carbon atoms, in whichthe alkyl group may be substituted with one or more substituentsselected from the group consisting of a hydroxyl group, a halogen atom,and an alkoxyl group having 1 to 6 carbon atoms; R⁴ and R⁵ eachindependently represents a hydrogen atom, a halogen atom, an alkyl grouphaving 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbonatoms, in which the alkyl group may be substituted with one or moresubstituents selected from the group consisting of a hydroxyl group, ahalogen atom, and an alkoxyl group having 1 to 6 carbon atoms; R⁶ and R⁷each independently represents a hydrogen atom or an alkyl group having 1to 6 carbon atoms; X₁ represents an oxygen atom, a sulfur atom, apartial structure:

 (wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or2)

(wherein R¹⁰ represents a hydrogen atom, a formyl group, an acyl grouphaving 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbonatoms); n represents an integer 1 or 2; and Q represents a partialstructure represented by formula:

 (wherein R¹¹ represents an alkyl group having 1 to 6 carbon atoms, analkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1to 6 carbon atoms, a substituted or unsubstituted cycloalkyl grouphaving 3 to 6 carbon atoms, a phenyl, a pyridyl or pyrimidinyl, analkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having1 to 6 carbon atoms; R¹² represents a hydrogen atom or an alkylthiogroup having 1 to 6 carbon atoms; R¹¹ and R¹² may be taken together withpart of the mother skeleton to which they are bonded to form a cyclicstructure that may have a sulfur atom as a ring-constituting atom and analkyl group having 1 to 6 carbon atoms as a substituent; R¹³ representsa hydrogen atom, an amino group, a hydroxyl group, a thiol group, ahalogenomethyl group, an alkyl group having 1 to 6 carbon atoms, analkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in whichthe amino group may have one or two substituents selected from the groupconsisting of a formyl group, an alkyl group having 1 to 6 carbon atoms,and an acyl group having 2 to 5 carbon atoms; X² represents a halogenatom or a hydrogen atom; A¹ represents a partial structure representedby formula (II):

 (wherein X³ represents a hydrogen atom, an amino group, a halogen atom,a cyano group, a halogenomethyl group, a halogenomethoxyl group, analkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxylgroup having 1 to 6 carbon atoms, in which the amino group may have oneor two substituents selected from the group consisting of a formylgroup, an alkyl group having 1 to 6 carbon atoms and an acyl grouphaving 2 to 5 carbon atoms; and X³ and R¹¹ maybe taken together withpart of the mother skeleton to which they are bonded to form a cyclicstructure that may contain an oxygen atom, a nitrogen atom or a sulfuratom as a ring-constituting atom and an alkyl group having 1 to 6 carbonatoms as a substituent); A² represents a nitrogen atom and A³ representsa carbon atom provided that A², A³ and the carbon atom to which they arebonded form a partial structure: >C═C(A¹═)—N(R¹¹)— and Y represents ahydrogen atom, a phenyl group, an acetoxymethyl group, apivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, adimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group,an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having2 to 7 carbon atoms, or a phenylalkyl group composed of an alkylenegroup having 1 to 6 carbon atoms and a phenyl group),  a salt or hydratethereof, or a hydrate of the salt.
 2. The compound according to claim 1,wherein Q is a structure represented by formula:

or a structure represented by formula:

a salt or hydrate thereof, or a hydrate of the salt.
 3. The compoundaccording to claim 1, wherein Q is a structure represented by formula:

a salt or hydrate thereof, or a hydrate of the salt.
 4. The compoundaccording to claim 1, wherein Q is a9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-6-carboxylicacid 10-yl group, a salt or hydrate thereof, or a hydrate of the salt.5. The compound according to claim 1, wherein Q is a6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinolin-3-carboxylicacid-7-yl group, a salt or hydrate thereof, or a hydrate of the salt. 6.The compound according to claim 1, wherein Q is a6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro4-oxoquinolin-3-carboxylicacid-7-yl group, a salt or hydrate thereof, or a hydrate of the salt. 7.The compound according to claim 1, wherein Q is a5-amino-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinolin-3-carboxylicacid-7-yl group, a salt or hydrate thereof, or a hydrate of the salt. 8.The compound according to claim 1, 2, 3, 4, 5, 6 or 7, wherein X¹ is apartial structure represented by formula:

wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or2, a salt or hydrate thereof, or a hydrate of the salt.
 9. The compoundaccording to claim 8, wherein R⁸ and R⁹ are each a hydrogen atom, and mis 1, a salt or hydrate thereof, or a hydrate of the salt.
 10. Thecompound according to claim 1, 2, 3, 4, 5, 6 or 7, wherein n is aninteger 1, a salt or hydrate thereof, or a hydrate of the salt.
 11. Thecompound according to claim 1, 2, 3, 4, 5, 6 or 7, wherein n is 1, andX¹ is a partial structure represented by formula:

wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms, and m represents an integer 1 or2, a salt or hydrate thereof, or a hydrate of the salt.
 12. The compoundaccording to claim 11, wherein R⁸ and R⁹ are each a hydrogen atom, asalt or hydrate thereof, or a hydrate of the salt.
 13. The compoundaccording to claim 11, wherein m is 1, a salt or hydrate thereof, or ahydrate of the salt.
 14. The compound according to claim 11, wherein R⁸and R⁹ are each a hydrogen atom, and m is 1, a salt or hydrate thereof,or a hydrate of the salt.
 15. The compound according to claim 14 whichis a stereochemically pure compound, a salt or hydrate thereof, or ahydrate of the salt.
 16. The compound according to claim 1, 2, 3, 4, 5,6 or 7 which is a stereochemically pure compound, a salt or hydratethereof, or a hydrate of the salt.
 17. The compound according to claim1,2, or 3, wherein R¹¹ is a cyclopropyl group having a halogen atom as asubstituent, a salt or hydrate thereof, or a hydrate of the salt. 18.The compound according to claim 17, wherein said cyclopropyl grouphaving a halogen atom as a substituent is a 1,2-cis-halogenocyclopropylgroup, a salt or hydrate thereof or a hydrate of the salt.
 19. Thecompound according to claim 18, wherein said cyclopropyl group having ahalogen atom as a substituent is a stereochemically pure substituent, asalt or hydrate thereof, or a hydrate of the salt.
 20. The compoundaccording to claim 19, wherein said cyclopropyl group having a halogenatom as a substituent is a (1R, 2S)-2-halogenocyclopropyl group, a saltor hydrate thereof, or a hydrate of the salt.
 21. The compound accordingto claim 20, wherein the halogen atom of said cyclopropyl group having ahalogen atom as a substituent is a fluorine atom, a salt or hydratethereof, or a hydrate of the salt.
 22. The compound according to claim1, 2, 3, 4, 5, 6 or 7, wherein each of R³, R⁴, R⁵, R⁶ and R⁷ is ahydrogen atom, a salt or hydrate thereof, or a hydrate of the salt. 23.The compound according to claim 22, wherein n is 1, a salt or hydratethereof, or a hydrate of the salt.
 24. The compound according to claim23, wherein X¹ is a partial structure represented by formula:

wherein R⁸ and R⁹ each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; and m is an integer 1 or 2, asalt or hydrate thereof, or a hydrate of the salt.
 25. The compoundaccording to claim 24, wherein R⁸ and R⁹ are each a hydrogen atom, asalt or hydrate thereof, or a hydrate of the salt.
 26. The compoundaccording to claim 25, wherein m is 1, a salt or hydrate thereof, or ahydrate of the salt.
 27. The compound according to claim 26, wherein R¹and R² are each a hydrogen atom, a salt or hydrate thereof or a hydrateof the salt.
 28. A composition which comprises a therapeuticallyeffective amount of the compound according to claim 1, 2, 3, 4, 5, 6 or7, a salt or hydrate thereof, or a hydrate of the salt as an activeingredient and a pharmaceutically acceptable carrier.
 29. A method oftreating an infectious disease caused by a bacterial pathogen selectedfrom the group consisting of gram positive bacteria, gram negativebacteria, and quinolone-resistance bacteria, which comprisesadministering to a host in need of treatment a therapeutically effectiveamount of the compound according to claim 1, 2, 3, 4, 5, 6 or 7, a saltor hydrate thereof, or a hydrate of the salt and a pharmaceuticallyacceptable carrier.
 30. The compound of claim 1, wherein said compoundis5-amino-7-(1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, a salt or hydrate thereof, or a hydrate of the salt.
 31. Thecompound of claim 1, wherein said compound is10-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4]benzoxazine-6-carboxylicacid, a salt or hydrate thereof, or a hydrate of the salt.
 32. Thecompound of claim 1, wherein said compound is10-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7-pyrido[1.2.3.-de][1,4]benzoxazine-6-carboxylicacid, a salt or hydrate thereof, or a hydrate of the salt.
 33. Thecompound of claim 1, wherein said compound is10-{1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1.2.3.-de][1,4]benzoxazine-6-carboxylicacid, a salt or hydrate thereof, or a hydrate of the salt.
 34. Thecompound of claim 1, wherein said compound is7-{1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, a salt or hydrate thereof, or a hydrate of the salt.
 35. Thecompound of claim 1, wherein said compound is5-amino-7-{1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-4-carboxylicacid, a salt or hydrate thereof, or a hydrate of the salt.
 36. Thecompound of claim 1, wherein said compound is7-(1-amino-4-azatricyclo[6.1.0.0^(2,6)]nonan-4-yl)-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, a salt or hydrate thereof, or a hydrate of the salt.